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Xi R, Cao Y, Fu N, Sheng Y, Yu J, Li L, Zhang G, Wang F. Allosteric inhibition of the tyrosine phosphatase SHP2 enhances the anti-tumor immunity of interferon α through induction of caspase-1-mediated pyroptosis in renal cancer. Int Immunopharmacol 2024; 143:113498. [PMID: 39467353 DOI: 10.1016/j.intimp.2024.113498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 10/21/2024] [Accepted: 10/22/2024] [Indexed: 10/30/2024]
Abstract
Interferon alpha (IFNα) leads to therapeutic effects on various tumors, especially renal cell cancer (RCC), by directly protecting against tumors cell proliferation or indirectly inducing an anti-tumor immune response. However, new combination therapies are needed to enhance the efficacy of IFNα and reduce its adverse effects during long-term treatment. In this study, we found that the anti-proliferative effects of IFNα on RCC cells in vitro and in vivo were greater after the allosteric inhibition of SHP2 by SHP099 than after treatment with enzymatic inhibitors of SHP2. SHP099 increased IFNα-induced pro-caspase-1 expression in RCC cells, activated the NLRP3 inflammasome, and induced pyroptosis. Mechanistically, SHP099 not only increased the expression of NLRP3 inflammasome components via the NF-κB signaling pathway, but also further activated the NLRP3 inflammasome by regulating mitochondrial homeostasis through ANT1-mediated reactive oxygen species modulation. Allosteric inhibition of SHP2 by SHP099 also potently enhanced the anti-tumor immunity induced by IFNα by modulating T cell proliferation and infiltration in vitro and in vivo. These results reveal the new function of SHP2 in NLRP3 inflammasome activation and pyroptosis in RCC and provide a basis for further investigating the combination of allosteric SHP2 inhibitors with IFNα in cancer immunotherapy.
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Affiliation(s)
- Ruiying Xi
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610213, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yu Cao
- State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Naijie Fu
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610213, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yuwen Sheng
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610213, China
| | - Jialing Yu
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610213, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Lingyu Li
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610213, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Guolin Zhang
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610213, China
| | - Fei Wang
- Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610213, China.
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Pandey G, Mazzacurati L, Rowsell TM, Horvat NP, Amin NE, Zhang G, Akuffo AA, Colin-Leitzinger CM, Haura EB, Kuykendall AT, Zhang L, Epling-Burnette PK, Reuther GW. SHP2 inhibition displays efficacy as a monotherapy and in combination with JAK2 inhibition in preclinical models of myeloproliferative neoplasms. Am J Hematol 2024; 99:1040-1055. [PMID: 38440831 PMCID: PMC11096011 DOI: 10.1002/ajh.27282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 01/30/2024] [Accepted: 02/19/2024] [Indexed: 03/06/2024]
Abstract
Myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocytosis, and primary myelofibrosis, are clonal hematopoietic neoplasms driven by mutationally activated signaling by the JAK2 tyrosine kinase. Although JAK2 inhibitors can improve MPN patients' quality of life, they do not induce complete remission as disease-driving cells persistently survive therapy. ERK activation has been highlighted as contributing to JAK2 inhibitor persistent cell survival. As ERK is a component of signaling by activated RAS proteins and by JAK2 activation, we sought to inhibit RAS activation to enhance responses to JAK2 inhibition in preclinical MPN models. We found the SHP2 inhibitor RMC-4550 significantly enhanced growth inhibition of MPN cell lines in combination with the JAK2 inhibitor ruxolitinib, effectively preventing ruxolitinib persistent growth, and the growth and viability of established ruxolitinib persistent cells remained sensitive to SHP2 inhibition. Both SHP2 and JAK2 inhibition diminished cellular RAS-GTP levels, and their concomitant inhibition enhanced ERK inactivation and increased apoptosis. Inhibition of SHP2 inhibited the neoplastic growth of MPN patient hematopoietic progenitor cells and exhibited synergy with ruxolitinib. RMC-4550 antagonized MPN phenotypes and increased survival of an MPN mouse model driven by MPL-W515L. The combination of RMC-4550 and ruxolitinib, which was safe and tolerated in healthy mice, further inhibited disease compared to ruxolitinib monotherapy, including extending survival. Given SHP2 inhibitors are undergoing clinical evaluation in patients with solid tumors, our preclinical findings suggest that SHP2 is a candidate therapeutic target with potential for rapid translation to clinical assessment to improve current targeted therapies for MPN patients.
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Affiliation(s)
- Garima Pandey
- Department of Molecular Oncology, Moffitt Cancer Center, Tampa, FL USA
| | - Lucia Mazzacurati
- Department of Molecular Oncology, Moffitt Cancer Center, Tampa, FL USA
| | - Tegan M. Rowsell
- Department of Molecular Oncology, Moffitt Cancer Center, Tampa, FL USA
| | | | - Narmin E. Amin
- Department of Molecular Oncology, Moffitt Cancer Center, Tampa, FL USA
| | - Guolin Zhang
- Department of Thoracic Oncology, Moffitt Cancer Center, Tampa, FL USA
| | - Afua A. Akuffo
- Department of Immunology, Moffitt Cancer Center, Tampa, FL USA
| | | | - Eric B. Haura
- Department of Thoracic Oncology, Moffitt Cancer Center, Tampa, FL USA
| | | | - Ling Zhang
- Department of Pathology, Moffitt Cancer Center, Tampa, FL USA
| | | | - Gary W. Reuther
- Department of Molecular Oncology, Moffitt Cancer Center, Tampa, FL USA
- Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL USA
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Chen X, Keller SJ, Hafner P, Alrawashdeh AY, Avery TY, Norona J, Zhou J, Ruess DA. Tyrosine phosphatase PTPN11/SHP2 in solid tumors - bull's eye for targeted therapy? Front Immunol 2024; 15:1340726. [PMID: 38504984 PMCID: PMC10948527 DOI: 10.3389/fimmu.2024.1340726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2023] [Accepted: 02/19/2024] [Indexed: 03/21/2024] Open
Abstract
Encoded by PTPN11, the Src-homology 2 domain-containing phosphatase 2 (SHP2) integrates signals from various membrane-bound receptors such as receptor tyrosine kinases (RTKs), cytokine and integrin receptors and thereby promotes cell survival and proliferation. Activating mutations in the PTPN11 gene may trigger signaling pathways leading to the development of hematological malignancies, but are rarely found in solid tumors. Yet, aberrant SHP2 expression or activation has implications in the development, progression and metastasis of many solid tumor entities. SHP2 is involved in multiple signaling cascades, including the RAS-RAF-MEK-ERK-, PI3K-AKT-, JAK-STAT- and PD-L1/PD-1- pathways. Although not mutated, activation or functional requirement of SHP2 appears to play a relevant and context-dependent dichotomous role. This mostly tumor-promoting and infrequently tumor-suppressive role exists in many cancers such as gastrointestinal tumors, pancreatic, liver and lung cancer, gynecological entities, head and neck cancers, prostate cancer, glioblastoma and melanoma. Recent studies have identified SHP2 as a potential biomarker for the prognosis of some solid tumors. Based on promising preclinical work and the advent of orally available allosteric SHP2-inhibitors early clinical trials are currently investigating SHP2-directed approaches in various solid tumors, either as a single agent or in combination regimes. We here provide a brief overview of the molecular functions of SHP2 and collate current knowledge with regard to the significance of SHP2 expression and function in different solid tumor entities, including cells in their microenvironment, immune escape and therapy resistance. In the context of the present landscape of clinical trials with allosteric SHP2-inhibitors we discuss the multitude of opportunities but also limitations of a strategy targeting this non-receptor protein tyrosine phosphatase for treatment of solid tumors.
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Affiliation(s)
- Xun Chen
- Department of General and Visceral Surgery, Center for Surgery, Medical Center University of Freiburg, Freiburg, Germany
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou, China
| | - Steffen Johannes Keller
- Department of General and Visceral Surgery, Center for Surgery, Medical Center University of Freiburg, Freiburg, Germany
| | - Philipp Hafner
- Department of General and Visceral Surgery, Center for Surgery, Medical Center University of Freiburg, Freiburg, Germany
| | - Asma Y. Alrawashdeh
- Department of General and Visceral Surgery, Center for Surgery, Medical Center University of Freiburg, Freiburg, Germany
| | - Thomas Yul Avery
- Department of General and Visceral Surgery, Center for Surgery, Medical Center University of Freiburg, Freiburg, Germany
| | - Johana Norona
- Department of General and Visceral Surgery, Center for Surgery, Medical Center University of Freiburg, Freiburg, Germany
- German Cancer Consortium (DKTK), Partner Site Freiburg and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Jinxue Zhou
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou, China
| | - Dietrich Alexander Ruess
- Department of General and Visceral Surgery, Center for Surgery, Medical Center University of Freiburg, Freiburg, Germany
- German Cancer Consortium (DKTK), Partner Site Freiburg and German Cancer Research Center (DKFZ), Heidelberg, Germany
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Celada SI, Lim CX, Carisey AF, Ochsner SA, Arce Deza CF, Rexie P, Poli De Frias F, Cardenas-Castillo R, Polverino F, Hengstschläger M, Tsoyi K, McKenna NJ, Kheradmand F, Weichhart T, Rosas IO, Van Kaer L, Celada LJ. SHP2 promotes sarcoidosis severity by inhibiting SKP2-targeted ubiquitination of TBET in CD8 + T cells. Sci Transl Med 2023; 15:eade2581. [PMID: 37703351 PMCID: PMC11126869 DOI: 10.1126/scitranslmed.ade2581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 08/24/2023] [Indexed: 09/15/2023]
Abstract
Sarcoidosis is an interstitial lung disease (ILD) characterized by interferon-γ (IFN-γ) and T-box expressed in T cells (TBET) dysregulation. Although one-third of patients progress from granulomatous inflammation to severe lung damage, the molecular mechanisms underlying this process remain unclear. Here, we found that pharmacological inhibition of phosphorylated SH2-containing protein tyrosine phosphatase-2 (pSHP2), a facilitator of aberrant IFN-γ abundance, decreased large granuloma formation and macrophage infiltration in the lungs of mice with sarcoidosis-like disease. Positive treatment outcomes were dependent on the effective enhancement of TBET ubiquitination within CD8+ T cells. Mechanistically, we identified a posttranslational modification pathway in which the E3 F-box protein S-phase kinase-associated protein 2 (SKP2) targets TBET for ubiquitination in T cells under normal conditions. However, this pathway was disrupted by aberrant pSHP2 signaling in CD8+ T cells from patients with progressive pulmonary sarcoidosis and end-stage disease. Ex vivo inhibition of pSHP2 in CD8+ T cells from patients with end-stage sarcoidosis enhanced TBET ubiquitination and suppressed IFN-γ and collagen synthesis. Therefore, these studies provided new mechanistic insights into the SHP2-dependent posttranslational regulation of TBET and identified SHP2 inhibition as a potential therapeutic intervention against severe sarcoidosis. Furthermore, these studies also suggest that the small-molecule SHP2 inhibitor SHP099 might be used as a therapeutic measure against human diseases linked to TBET or ubiquitination.
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Affiliation(s)
- Sherly I. Celada
- Department of Biological Sciences, Tennessee State University, Nashville, TN 37209, USA
| | - Clarice X. Lim
- Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria
| | - Alexandre F. Carisey
- William T. Shearer Center for Human Immunobiology, Texas Children’s Hospital, Houston, TX 77030, USA
- Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
- Department of Cell and Molecular Biology, St. Jude Children’s Hospital, Memphis, TN 38105, USA
| | - Scott A. Ochsner
- Department of Molecular and Cellular Biology, Houston, TX 77030, USA
| | - Carlos F. Arce Deza
- Department of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Praveen Rexie
- Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria
| | - Fernando Poli De Frias
- Department of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, TX 77030, USA
- Mout Sinai Medical Center, Miami Beach, FL 33140, USA
| | - Rafael Cardenas-Castillo
- Department of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Francesca Polverino
- Department of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Markus Hengstschläger
- Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria
| | - Konstantin Tsoyi
- Department of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Neil J. McKenna
- Department of Molecular and Cellular Biology, Houston, TX 77030, USA
| | - Farrah Kheradmand
- Department of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, TX 77030, USA
- Center for Translational Research on Inflammatory Diseases, Michael E. DeBakey, Houston, TX 77030, USA
| | - Thomas Weichhart
- Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria
| | - Ivan O. Rosas
- Department of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Luc Van Kaer
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232 USA
| | - Lindsay J. Celada
- Department of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, TX 77030, USA
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232 USA
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Chebolu A, Ramos RB, Arunachalam T, Adam AP, Wladis EJ. SH2 domain-containing protein tyrosine phosphatase-2 is enriched in eyelid specimens of rosacea. SKIN HEALTH AND DISEASE 2023; 3:e190. [PMID: 36751313 PMCID: PMC9892417 DOI: 10.1002/ski2.190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/24/2022] [Revised: 10/24/2022] [Accepted: 11/01/2022] [Indexed: 11/18/2022]
Abstract
Background Rosacea is a cutaneous disease that may secondarily affect the ocular surface. Due to the vision threatening, cosmetic, psychological, and work productivity impact, the identification of cellular targets that govern rosacea would enhance our understanding of the biology of the disease and delineate targets for therapeutic manipulation. Objective To characterize the involvement of SH2 domain-containing protein tyrosine phosphatase-2 (SHP2) in the pathogenesis of rosacea. Methods Specimens from elective ectropion surgery (n = 20) were processed from patients with rosacea (n = 10) and control patients (n = 10). Immunohistochemistry (IHC) and quantitative western blotting (WB) were performed to identify and quantify the presence of SHP2 and 4G10 (a phosphotyrosine antibody) in rosacea compared to normal tissue. IHC samples were graded according to an intensity scale (0-4). Mann-Whitney statistical analyses were performed via a dedicated computerized software package. Results On WB, SHP2 was expressed in higher concentrations in rosacea specimens (p < 0.05). On IHC, SHP2 was enriched in the epidermis in rosacea (p < 0.05), although 4G10 levels were not statistically significantly different between the two groups (p > 0.05). Conclusions SHP2 is enriched in cutaneous specimens of rosacea, suggesting a critical role for this protein in the disease and indicating a modifiable therapeutic moiety.
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Affiliation(s)
- Apoorv Chebolu
- Department of OphthalmologyLions Eye InstituteAlbanyNew YorkUSA
| | - Ramon Bossardi Ramos
- Department of Molecular and Cellular PhysiologyAlbany Medical CenterAlbanyNew YorkUSA
| | | | - Alejandro Pablo Adam
- Department of Molecular and Cellular PhysiologyAlbany Medical CenterAlbanyNew YorkUSA
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Asmamaw MD, Shi XJ, Zhang LR, Liu HM. A comprehensive review of SHP2 and its role in cancer. Cell Oncol 2022; 45:729-753. [PMID: 36066752 DOI: 10.1007/s13402-022-00698-1] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/26/2022] [Indexed: 12/26/2022] Open
Abstract
Src homology 2-containing protein tyrosine phosphatase 2 (SHP2) is a non-receptor protein tyrosine phosphatase ubiquitously expressed mainly in the cytoplasm of several tissues. SHP2 modulates diverse cell signaling events that control metabolism, cell growth, differentiation, cell migration, transcription and oncogenic transformation. It interacts with diverse molecules in the cell, and regulates key signaling events including RAS/ERK, PI3K/AKT, JAK/STAT and PD-1 pathways downstream of several receptor tyrosine kinases (RTKs) upon stimulation by growth factors and cytokines. SHP2 acts as both a phosphatase and a scaffold, and plays prominently oncogenic functions but can be tumor suppressor in a context-dependent manner. It typically acts as a positive regulator of RTKs signaling with some inhibitory functions reported as well. SHP2 expression and activity is regulated by such factors as allosteric autoinhibition, microRNAs, ubiquitination and SUMOylation. Dysregulation of SHP2 expression or activity causes many developmental diseases, and hematological and solid tumors. Moreover, upregulated SHP2 expression or activity also decreases sensitivity of cancer cells to anticancer drugs. SHP2 is now considered as a compelling anticancer drug target and several classes of SHP2 inhibitors with different mode of action are developed with some already in clinical trial phases. Moreover, novel SHP2 substrates and functions are rapidly growing both in cell and cancer. In view of this, we comprehensively and thoroughly reviewed literatures about SHP2 regulatory mechanisms, substrates and binding partners, biological functions, roles in human cancers, and different classes of small molecule inhibitors target this oncoprotein in cancer.
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Affiliation(s)
- Moges Dessale Asmamaw
- Department of Pharmacology, School of Basic Medical Sciences, State Key Laboratory for Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, Henan Province, 450001, People's Republic of China
| | - Xiao-Jing Shi
- Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan Province, 450052, People's Republic of China
| | - Li-Rong Zhang
- Department of Pharmacology, School of Basic Medical Sciences, State Key Laboratory for Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, Henan Province, 450001, People's Republic of China.
| | - Hong-Min Liu
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, Henan Province, China. .,Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou, Henan Province, 450001, People's Republic of China.
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Takagane K, Umakoshi M, Itoh G, Kuriyama S, Goto A, Tanaka M. SKAP2 suppresses inflammation-mediated tumorigenesis by regulating SHP-1 and SHP-2. Oncogene 2022; 41:1087-1099. [PMID: 35034964 DOI: 10.1038/s41388-021-02153-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 12/01/2021] [Accepted: 12/09/2021] [Indexed: 12/29/2022]
Abstract
Inflammatory bowel diseases, like ulcerative colitis and Crohn's disease are frequently accompanied by colorectal cancers. However, the mechanisms underlying colitis-associated cancers are not fully understood. Src Kinase Associated Phosphoprotein 2 (SKAP2), a substrate of Src family kinases, is highly expressed in macrophages. Here, we examined the effects of SKAP2 on inflammatory responses in a mouse model of tumorigenesis with colitis induced by azoxymethane/dextran sulfate sodium. SKAP2 knockout increased the severity of colitis and tumorigenesis, as well as lipopolysaccharide (LPS) induced acute inflammation. SKAP2 attenuated inflammatory signaling in macrophages induced by uptake of cancer cell-derived exosomes. SKAP2-/- mice were characterized by the activation of NF-κB signaling and the upregulation and release of cytokines including TNFα, IL-1β, IL-6, CXCL-9/-10/-13, and sICAM1; SKAP2 overexpression attenuated NF-κB activation. Mechanistically, SKAP2 formed a complex with the SHP-1 tyrosine phosphatase via association with the Sirpα transmembrane receptor. SKAP2 also physically associated with the TIR domain of MyD88, TIRAP, and TRAM, adaptors of toll-like receptor 4 (TLR4). SKAP2-mediated recruitment of the Sirpα/SHP-1 complex to TLR4 attenuated inflammatory responses, whereas direct interaction of SKAP2 with SHP-2 decreased SHP-2 activation. SHP-2 is required for efficient NF-κB activation and suppresses the TRAM/TRIF-INFβ pathway; therefore, SKAP2-mediated SHP-2 inhibition affected two signaling axes from TLR4. The present findings indicate that SKAP2 prevents excess inflammation by inhibiting the TLR4-NF-κB pathway, and it activates the TLR4-IFNβ pathway through SHP-1 and SHP-2, thereby suppressing inflammation-mediated tumorigenesis.
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Affiliation(s)
- Kurara Takagane
- Department of Molecular Medicine and Biochemistry, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan
- Technical Division, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan
| | - Michinobu Umakoshi
- Department of Cellular and Organ Pathology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan
| | - Go Itoh
- Department of Molecular Medicine and Biochemistry, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan
| | - Sei Kuriyama
- Department of Molecular Medicine and Biochemistry, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan
| | - Akiteru Goto
- Department of Cellular and Organ Pathology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan
| | - Masamitsu Tanaka
- Department of Molecular Medicine and Biochemistry, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan.
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Gunther RC, Bharathi V, Miles SD, Tumey LR, Schmedes CM, Tatsumi K, Bridges MD, Martinez D, Montgomery SA, Beck MA, Camerer E, Mackman N, Antoniak S. Myeloid Protease-Activated Receptor-2 Contributes to Influenza A Virus Pathology in Mice. Front Immunol 2021; 12:791017. [PMID: 34925374 PMCID: PMC8671937 DOI: 10.3389/fimmu.2021.791017] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 11/12/2021] [Indexed: 11/13/2022] Open
Abstract
BackgroundInnate immune responses to influenza A virus (IAV) infection are initiated in part by toll-like receptor 3 (TLR3). TLR3-dependent signaling induces an antiviral immune response and an NFκB-dependent inflammatory response. Protease-activated receptor 2 (PAR2) inhibits the antiviral response and enhances the inflammatory response. PAR2 deficiency protected mice during IAV infection. However, the PAR2 expressing cell-types contributing to IAV pathology in mice and the mechanism by which PAR2 contributes to IAV infection is unknown.MethodsIAV infection was analyzed in global (Par2-/-), myeloid (Par2fl/fl;LysMCre+) and lung epithelial cell (EpC) Par2 deficient (Par2fl/fl;SPCCre+) mice and their respective controls (Par2+/+ and Par2fl/fl). In addition, the effect of PAR2 activation on polyinosinic-polycytidylic acid (poly I:C) activation of TLR3 was analyzed in bone marrow-derived macrophages (BMDM). Lastly, we determined the effect of PAR2 inhibition in wild-type (WT) mice.ResultsAfter IAV infection, Par2-/- and mice with myeloid Par2 deficiency exhibited increased survival compared to infected controls. The improved survival was associated with reduced proinflammatory mediators and reduced cellular infiltration in bronchoalveolar lavage fluid (BALF) of Par2-/- and Par2fl/fl;LysMCre+ 3 days post infection (dpi) compared to infected control mice. Interestingly, Par2fl/fl;SPCCre+ mice showed no survival benefit compared to Par2fl/fl. In vitro studies showed that Par2-/- BMDM produced less IL6 and IL12p40 than Par2+/+ BMDM after poly I:C stimulation. In addition, activation of PAR2 on Par2+/+ BMDM increased poly I:C induction of IL6 and IL12p40 compared to poly I:C stimulation alone. Importantly, PAR2 inhibition prior to IAV infection protect WT mice.ConclusionGlobal Par2 or myeloid cell but not lung EpC Par2 deficiency was associated with reduced BALF inflammatory markers and reduced IAV-induced mortality. Our study suggests that PAR2 may be a therapeutic target to reduce IAV pathology.
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Affiliation(s)
- Randall C. Gunther
- UNC Blood Research Center, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Vanthana Bharathi
- UNC Blood Research Center, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Stephen D. Miles
- UNC Blood Research Center, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Lauryn R. Tumey
- UNC Blood Research Center, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Clare M. Schmedes
- UNC Blood Research Center, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Kohei Tatsumi
- UNC Blood Research Center, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Meagan D. Bridges
- UNC Blood Research Center, Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - David Martinez
- UNC Blood Research Center, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Stephanie A. Montgomery
- UNC Lineberger Comprehensive Cancer Center, Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Melinda A. Beck
- Department of Nutrition, Gillings School of Global Public Health, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Eric Camerer
- Department of Medicine, Université de Paris, Paris Cardiovascular Research Center (PARCC), INSERM UMR 970, Paris, France
| | - Nigel Mackman
- UNC Blood Research Center, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Silvio Antoniak
- UNC Blood Research Center, UNC Lineberger Comprehensive Cancer Center, UNC McAllister Heart Institute, Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- *Correspondence: Silvio Antoniak,
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Mirzaei R, Gordon A, Zemp FJ, Kumar M, Sarkar S, Luchman HA, Bellail AC, Hao C, Mahoney DJ, Dunn JF, Bose P, Yong VW. PD-1 independent of PD-L1 ligation promotes glioblastoma growth through the NFκB pathway. SCIENCE ADVANCES 2021; 7:eabh2148. [PMID: 34739319 PMCID: PMC8570610 DOI: 10.1126/sciadv.abh2148] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/05/2023]
Abstract
Brain tumor–initiating cells (BTICs) drive glioblastoma growth through not fully understood mechanisms. Here, we found that about 8% of cells within the human glioblastoma microenvironment coexpress programmed cell death 1 (PD-1) and BTIC marker. Gain- or loss-of-function studies revealed that tumor-intrinsic PD-1 promoted proliferation and self-renewal of BTICs. Phosphorylation of tyrosines within the cytoplasmic tail of PD-1 recruited Src homology 2–containing phosphatase 2 and activated the nuclear factor kB in BTICs. Notably, the tumor-intrinsic promoting effects of PD-1 did not require programmed cell death ligand 1(PD-L1) ligation; thus, the therapeutic antibodies inhibiting PD-1/PD-L1 interaction could not overcome the growth advantage of PD-1 in BTICs. Last, BTIC-intrinsic PD-1 accelerated intracranial tumor growth, and this occurred in mice lacking T and B cells. These findings point to a critical role for PD-1 in BTICs and uncover a nonimmune resistance mechanism of patients with glioblastoma to PD-1– or PD-L1–blocking therapies.
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Affiliation(s)
- Reza Mirzaei
- Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada
- Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
| | - Ashley Gordon
- Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada
- Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
| | - Franz J. Zemp
- Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada
- Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada
| | - Mehul Kumar
- Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada
- Department of Oncology, University of Calgary, Calgary, Alberta, Canada
| | - Susobhan Sarkar
- Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada
- Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
| | - H. Artee Luchman
- Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
- Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada
| | - Anita C. Bellail
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Chunhai Hao
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Douglas J. Mahoney
- Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada
- Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada
- Department of Microbiology, Immunology, and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada
- Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada
| | - Jeff F. Dunn
- Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada
- Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
- Department of Radiology, University of Calgary, Calgary, Alberta, Canada
| | - Pinaki Bose
- Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
- Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada
- Department of Oncology, University of Calgary, Calgary, Alberta, Canada
- Department of Surgery, University of Calgary, Calgary, Alberta, Canada
| | - V. Wee Yong
- Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada
- Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
- Department of Oncology, University of Calgary, Calgary, Alberta, Canada
- Corresponding author.
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10
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Double-edged roles of protein tyrosine phosphatase SHP2 in cancer and its inhibitors in clinical trials. Pharmacol Ther 2021; 230:107966. [PMID: 34403682 DOI: 10.1016/j.pharmthera.2021.107966] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 07/09/2021] [Accepted: 07/20/2021] [Indexed: 12/13/2022]
Abstract
Phosphorylation is a reversible post-translational modification regulated by phosphorylase and dephosphorylase to mediate important cellular events. Src homology-2-containing protein tyrosine phosphatase 2 (SHP2) encoded by PTPN11 is the first identified oncogenic protein in protein tyrosine phosphatases family. Serving as a convergent node, SHP2 is involved in multiple cascade signaling pathways including Ras-Raf-MEK-ERK, PI3K-AKT, JAK-STAT and PD-1/PD-L1 pathways. Especially, the double-edged roles of SHP2 based on the substrate specificity in various biological contexts dramatically increase the effect complexity in different SHP2-associated diseases. Evidences suggest that by collaborating with other mutations in associated pathways, dysregulation of SHP2 contributes to the pathogenesis of different cancers, making SHP2 a promising therapeutic target for cancer treatment. SHP2 can either act as oncogenic factor or tumor suppressor in different diseases, and both the conserved catalytic dephosphorylation mechanism and the unique allosteric regulation mechanism of SHP2 provide opportunities for the development of SHP2 inhibitors and activators. To date, several small-molecule SHP2 inhibitors have advanced into clinical trials for mono- or combined therapy of cancers. Moreover, SHP2 activators and proteolysis-targeting chimera (PROTAC)-based degraders also display therapeutic promise. In this review, we comprehensively summarize the overall structures, regulation mechanisms, double-edged roles of SHP2 in both physiological and carcinogenic pathways, and SHP2 inhibitors in clinical trials. SHP2 activators and degraders are also briefly discussed. This review aims to provide in-depth understanding of the biological roles of SHP2 and highlight therapeutic potential of targeting SHP2.
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11
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Kondreddy V, Magisetty J, Keshava S, Rao LVM, Pendurthi UR. Gab2 (Grb2-Associated Binder2) Plays a Crucial Role in Inflammatory Signaling and Endothelial Dysfunction. Arterioscler Thromb Vasc Biol 2021; 41:1987-2005. [PMID: 33827252 PMCID: PMC8147699 DOI: 10.1161/atvbaha.121.316153] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 03/19/2021] [Indexed: 01/21/2023]
Abstract
[Figure: see text].
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Affiliation(s)
- Vijay Kondreddy
- Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler
| | - Jhansi Magisetty
- Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler
| | - Shiva Keshava
- Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler
| | - L. Vijaya Mohan Rao
- Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler
| | - Usha R. Pendurthi
- Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler
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12
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Zhou H, Li N, Yuan Y, Jin YG, Wu Q, Yan L, Bian ZY, Deng W, Shen DF, Li H, Tang QZ. Leukocyte immunoglobulin-like receptor B4 protects against cardiac hypertrophy via SHP-2-dependent inhibition of the NF-κB pathway. J Mol Med (Berl) 2020; 98:691-705. [PMID: 32280997 DOI: 10.1007/s00109-020-01896-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 03/08/2020] [Accepted: 03/11/2020] [Indexed: 10/24/2022]
Abstract
Cardiac hypertrophy is a complex pathological process, and the molecular mechanisms underlying hypertrophic remodeling have not been clearly elucidated. Leukocyte immunoglobulin-like receptor B4 (lilrb4) is an inhibitory transmembrane protein that is necessary for the regulation of various cellular signaling pathways. To investigate whether lilrb4 plays a role in cardiac hypertrophy, we performed aortic banding in lilrb4 knockout mice, lilrb4 cardiac-specific transgenic mice, and their wild-type littermates. Cardiac hypertrophy was evaluated by echocardiographic, hemodynamic, pathological, and molecular analyses. We found that lilrb4 was expressed both in myocardial tissue and on cultured cardiomyocytes under basal conditions, but the expression was obviously decreased in mouse hearts following aortic banding and in cardiomyocytes treated with angiotensin II. Lilrb4 disruption aggravated cardiac hypertrophy, fibrosis, and dysfunction in response to pressure overload. Conversely, the cardiac overexpression of lilrb4 led to the opposite effects. Moreover, lilrb4 overexpression inhibited angiotensin II-induced cardiomyocyte hypertrophy in vitro. Mechanistically, we determined that the cardioprotective effect of lilrb4 was mediated through an interaction with SHP-2, the preservation of phosphorylated SHP-2, and the inhibition of the NF-κB pathway. In addition, SHP-2 knockdown in cardiomyocytes eliminated the inhibitory effects of lilrb4 on angiotensin II-induced hypertrophy and NF-κB activation. Our results suggest that lilrb4 protects against pathological cardiac hypertrophy via the SHP-2-dependent inhibition of the NF-κB pathway and may act as a potential therapeutic target for cardiac hypertrophy. KEY MESSAGES: Lilrb4 expression is decreased by hypertrophic stimuli. Lilrb4 protects against pathological cardiac hypertrophy. Lilrb4 interacts with SHP-2 and inhibits NF-κB pathway.
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Affiliation(s)
- Heng Zhou
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China.,Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, People's Republic of China.,Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, People's Republic of China
| | - Ning Li
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China.,Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, People's Republic of China.,Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, People's Republic of China
| | - Yuan Yuan
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China.,Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, People's Republic of China.,Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, People's Republic of China
| | - Ya-Ge Jin
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China.,Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, People's Republic of China.,Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, People's Republic of China
| | - Qingqing Wu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China.,Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, People's Republic of China.,Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, People's Republic of China
| | - Ling Yan
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China.,Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, People's Republic of China.,Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, People's Republic of China
| | - Zhou-Yan Bian
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China.,Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, People's Republic of China.,Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, People's Republic of China
| | - Wei Deng
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China.,Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, People's Republic of China.,Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, People's Republic of China
| | - Di-Fei Shen
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China.,Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, People's Republic of China.,Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, People's Republic of China
| | - Hongliang Li
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China.,Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, People's Republic of China.,Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, People's Republic of China
| | - Qi-Zhu Tang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China. .,Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, People's Republic of China. .,Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, People's Republic of China.
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13
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Therapeutic potential of targeting SHP2 in human developmental disorders and cancers. Eur J Med Chem 2020; 190:112117. [PMID: 32061959 DOI: 10.1016/j.ejmech.2020.112117] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 02/03/2020] [Accepted: 02/03/2020] [Indexed: 02/06/2023]
Abstract
Src homology 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2), encoded by PTPN11, regulates cell proliferation, differentiation, apoptosis and survival via releasing intramolecular autoinhibition and modulating various signaling pathways, such as mitogen-activated protein kinase (MAPK) pathway. Mutations and aberrant expression of SHP2 are implicated in human developmental disorders, leukemias and several solid tumors. As an oncoprotein in some cancers, SHP2 represents a rational target for inhibitors to interfere. Nevertheless, its tumor suppressive effect has also been uncovered, indicating the context-specificity. Even so, two types of SHP2 inhibitors including targeting catalytic pocket and allosteric sites have been developed associated with resolved cocrystal complexes. Herein, we describe its structure, biological function, deregulation in human diseases and summarize recent advance in development of SHP2 inhibitors, trying to give an insight into the therapeutic potential in future.
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14
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Gagné-Sansfacon J, Langlois A, Langlois MJ, Coulombe G, Tremblay S, Vaillancourt-Lavigueur V, Qu CK, Menendez A, Rivard N. The tyrosine phosphatase Shp-2 confers resistance to colonic inflammation by driving goblet cell function and crypt regeneration. J Pathol 2018; 247:135-146. [PMID: 30376595 PMCID: PMC6519201 DOI: 10.1002/path.5177] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Revised: 08/30/2018] [Accepted: 12/25/2018] [Indexed: 12/18/2022]
Abstract
The Src homology‐2 domain‐containing tyrosine phosphatase 2 (SHP‐2) regulates many cellular processes, including proliferation, differentiation and survival. Polymorphisms in the gene encoding SHP‐2 are associated with an increased susceptibility to develop ulcerative colitis. We recently reported that intestinal epithelial cell (IEC)‐specific deletion of Shp‐2 in mice (Shp‐2IEC‐KO) leads to chronic colitis and colitis‐associated cancer. This suggests that SHP‐2‐dependent signaling protects the colonic epithelium against inflammation and colitis‐associated cancer development. To verify this hypothesis, we generated mice expressing the Shp‐2 E76K activated form specifically in IEC. Our results showed that sustained Shp‐2 activation in IEC increased intestine and crypt length, correlating with increased cell proliferation and migration. Crypt regeneration capacity was also markedly enhanced, as revealed by ex vivo organoid culture. Shp‐2 activation alters the secretory cell lineage, as evidenced by increased goblet cell numbers and mucus secretion. Notably, these mice also demonstrated elevated ERK signaling in IEC and exhibited resistance against both chemical‐ and Citrobacter rodentium‐induced colitis. In contrast, mice with IEC‐specific Shp‐2 deletion displayed reduced ERK signaling and rapidly developed chronic colitis. Remarkably, expression of an activated form of Braf in Shp‐2‐deficient mice restored ERK activation, goblet cell production and prevented colitis. Altogether, our results indicate that chronic activation of Shp‐2/ERK signaling in the colonic epithelium confers resistance to mucosal erosion and colitis. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Jessica Gagné-Sansfacon
- Department of Anatomy and Cell Biology, Cancer Research Pavilion, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Canada
| | - Ariane Langlois
- Department of Anatomy and Cell Biology, Cancer Research Pavilion, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Canada
| | - Marie-Josée Langlois
- Department of Anatomy and Cell Biology, Cancer Research Pavilion, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Canada
| | - Geneviève Coulombe
- Department of Anatomy and Cell Biology, Cancer Research Pavilion, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Canada
| | - Sarah Tremblay
- Department of Microbiology and Infectiology, Cancer Research Pavilion, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Canada
| | - Vanessa Vaillancourt-Lavigueur
- Department of Anatomy and Cell Biology, Cancer Research Pavilion, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Canada
| | - Cheng-Kui Qu
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA
| | - Alfredo Menendez
- Department of Microbiology and Infectiology, Cancer Research Pavilion, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Canada
| | - Nathalie Rivard
- Department of Anatomy and Cell Biology, Cancer Research Pavilion, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Canada
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15
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Deng M, Gui X, Kim J, Xie L, Chen W, Li Z, He L, Chen Y, Chen H, Luo W, Lu Z, Xie J, Churchill H, Xu Y, Zhou Z, Wu G, Yu C, John S, Hirayasu K, Nguyen N, Liu X, Huang F, Li L, Deng H, Tang H, Sadek AH, Zhang L, Huang T, Zou Y, Chen B, Zhu H, Arase H, Xia N, Jiang Y, Collins R, You MJ, Homsi J, Unni N, Lewis C, Chen GQ, Fu YX, Liao XC, An Z, Zheng J, Zhang N, Zhang CC. LILRB4 signalling in leukaemia cells mediates T cell suppression and tumour infiltration. Nature 2018; 562:605-609. [PMID: 30333625 PMCID: PMC6296374 DOI: 10.1038/s41586-018-0615-z] [Citation(s) in RCA: 196] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2016] [Accepted: 08/15/2018] [Indexed: 12/18/2022]
Abstract
Immune checkpoint blockade therapy has been successful in treating some types of cancer but has not shown clinical benefits for treating leukaemia1. This result suggests that leukaemia uses unique mechanisms to evade this therapy. Certain immune inhibitory receptors that are expressed by normal immune cells are also present on leukaemia cells. Whether these receptors can initiate immune-related primary signalling in tumour cells remains unknown. Here we use mouse models and human cells to show that LILRB4, an immunoreceptor tyrosine-based inhibition motif-containing receptor and a marker of monocytic leukaemia, supports tumour cell infiltration into tissues and suppresses T cell activity via a signalling pathway that involves APOE, LILRB4, SHP-2, uPAR and ARG1 in acute myeloid leukaemia (AML) cells. Deletion of LILRB4 or the use of antibodies to block LILRB4 signalling impeded AML development. Thus, LILRB4 orchestrates tumour invasion pathways in monocytic leukaemia cells by creating an immunosuppressive microenvironment. LILRB4 represents a compelling target for the treatment of monocytic AML.
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MESH Headings
- Animals
- Apolipoproteins E/metabolism
- Arginase/metabolism
- CD4-Positive T-Lymphocytes/cytology
- CD4-Positive T-Lymphocytes/immunology
- CD8-Positive T-Lymphocytes/cytology
- CD8-Positive T-Lymphocytes/immunology
- Cell Movement
- Cell Proliferation
- Female
- Humans
- Immune Tolerance/immunology
- Leukemia, Myeloid, Acute/drug therapy
- Leukemia, Myeloid, Acute/immunology
- Leukemia, Myeloid, Acute/metabolism
- Leukemia, Myeloid, Acute/pathology
- Male
- Membrane Glycoproteins
- Mice
- Mice, Inbred C57BL
- Mice, Inbred NOD
- Mice, SCID
- Protein Binding
- Protein Tyrosine Phosphatase, Non-Receptor Type 11/metabolism
- Receptors, Cell Surface/deficiency
- Receptors, Cell Surface/genetics
- Receptors, Cell Surface/metabolism
- Receptors, Immunologic
- Receptors, Urokinase Plasminogen Activator/metabolism
- Signal Transduction
- Tumor Escape/drug effects
- Tumor Escape/immunology
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Mi Deng
- Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Xun Gui
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA
| | - Jaehyup Kim
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Li Xie
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weina Chen
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Zunling Li
- Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Taishan Immunology Program, Basic Medicine School, Binzhou Medical University, Yantai, China
| | - Licai He
- Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medical and Life Science, Wenzhou Medical University, Wenzhou, China
| | - Yuanzhi Chen
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA
- School of Public Health, Xiamen University, Xiamen, China
| | - Heyu Chen
- Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Weiguang Luo
- Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Department of Immunology, Xiangya Medical School, Central South University, Changsha, China
| | - Zhigang Lu
- Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Institute of Biomedical Sciences and the Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China
| | - Jingjing Xie
- Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Taishan Immunology Program, Basic Medicine School, Binzhou Medical University, Yantai, China
| | - Hywyn Churchill
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Yixiang Xu
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA
| | - Zhan Zhou
- Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Guojin Wu
- Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Chenyi Yu
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA
- Xiangya Medical School, Central South University, Changsha, China
| | - Samuel John
- Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Kouyuki Hirayasu
- Department of Immunochemistry, Research Institute for Microbial Diseases and Laboratory of Immunochemistry, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Nam Nguyen
- Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Xiaoye Liu
- Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Fangfang Huang
- Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Department of Hematology, Zhongshan Hospital, Xiamen University, Xiamen, China
| | - Leike Li
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA
| | - Hui Deng
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA
| | - Haidong Tang
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Ali H Sadek
- Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Lingbo Zhang
- Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Xiangya Medical School, Central South University, Changsha, China
| | - Tao Huang
- Immune-Onc Therapeutics, Inc., Palo Alto, CA, USA
| | - Yizhou Zou
- Department of Immunology, Xiangya Medical School, Central South University, Changsha, China
| | - Benjamin Chen
- Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Hong Zhu
- Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Hisashi Arase
- Department of Immunochemistry, Research Institute for Microbial Diseases and Laboratory of Immunochemistry, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Ningshao Xia
- School of Public Health, Xiamen University, Xiamen, China
| | - Youxing Jiang
- Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Robert Collins
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - M James You
- Department of Hematopathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jade Homsi
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Nisha Unni
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Cheryl Lewis
- Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Guo-Qiang Chen
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yang-Xin Fu
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | | | - Zhiqiang An
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA.
| | - Junke Zheng
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Ningyan Zhang
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA.
| | - Cheng Cheng Zhang
- Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
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16
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E3 Ubiquitin Ligase c-cbl Inhibits Microglia Activation After Chronic Constriction Injury. Neurochem Res 2018; 43:1631-1640. [PMID: 29934689 DOI: 10.1007/s11064-018-2578-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2017] [Revised: 06/12/2018] [Accepted: 06/15/2018] [Indexed: 12/11/2022]
Abstract
E3 ubiquitin ligase c-Caritas B cell lymphoma (c-cbl) is associated with negative regulation of receptor tyrosine kinases, signal transduction of antigens and cytokine receptors, and immune response. However, the expression and function of c-cbl in the regulation of neuropathic pain after chronic constriction injury (CCI) are unknown. In rat CCI model, c-cbl inhibited the activation of spinal cord microglia and the release of pro-inflammatory factors including tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β) and interleukin 6 (IL-6), which alleviated mechanical and heat pain through down-regulating extracellular signal-regulated kinase (ERK) pathway. Additionally, exogenous TNF-α inhibited c-cbl protein level vice versa. In the primary microglia transfected with c-cbl siRNA, when treated with TNF-α or TNF-α inhibitor, the corresponding secretion of IL-1β and IL-6 did not change. In summary, CCI down-regulated c-cbl expression and induced the activation of microglia, then activated microglia released inflammatory factors via ERK signaling to cause pain. Our data might supply a novel molecular target for the therapy of CCI-induced neuropathic pain.
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17
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Huang Y, Wang J, Cao F, Jiang H, Li A, Li J, Qiu L, Shen H, Chang W, Zhou C, Pan Y, Lu Y. SHP2 associates with nuclear localization of STAT3: significance in progression and prognosis of colorectal cancer. Sci Rep 2017; 7:17597. [PMID: 29242509 PMCID: PMC5730547 DOI: 10.1038/s41598-017-17604-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Accepted: 11/28/2017] [Indexed: 12/11/2022] Open
Abstract
Tyrosine phosphatase SHP2, encoded by PTPN11, has been implicated in many physiologic and pathologic processes in neoplastic progression. However, controversies are emerging from many studies, indicating SHP2 has a dual role in different types of tumors. We aimed to explore the role of SHP2 in progression and prognosis of colorectal cancer (CRC). SHP2 inhibited CRC cell proliferation and migration, and the phosphorylation of STAT3 was negatively regulated by SHP2 in CRC. SHP2 and nuclear STAT3 were examined in 270 CRC tissues. SHP2 was significantly correlated with nuclear STAT3 (Spearman’s rho = −0.408, P ≤ 0.001). Based on Cox regression analysis, patients with high levels of SHP2 and low levels of nuclear STAT3 had longer disease-specific survival (DSS) (HR, 0.362; 95% CI, 0.165–0.794) and disease-free survival (DFS) (HR, 0.447; 95% CI, 0.227–0.877). Further, low levels of SHP2 and high levels of nuclear STAT3 were independently associated with adverse outcomes in the whole cohort (DFS; HR, 2.353; 95% CI, 1.199–4.619). These results suggest that combination of SHP2 and nuclear STAT3 is a strong prognostic predictor in CRC.
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Affiliation(s)
- Yan Huang
- Department of Biochemical Pharmacy, School of Pharmacy, Second Military Medical University, Shanghai, 200433, China
| | - Jie Wang
- Department of Biochemical Pharmacy, School of Pharmacy, Second Military Medical University, Shanghai, 200433, China
| | - Fuao Cao
- Department of colorectal surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China
| | - Hailong Jiang
- Department of Biochemical Pharmacy, School of Pharmacy, Second Military Medical University, Shanghai, 200433, China
| | - An Li
- Department of Biochemical Pharmacy, School of Pharmacy, Second Military Medical University, Shanghai, 200433, China
| | - Jianzhong Li
- Department of Biochemical Pharmacy, School of Pharmacy, Second Military Medical University, Shanghai, 200433, China
| | - Lei Qiu
- Department of Biochemical Pharmacy, School of Pharmacy, Second Military Medical University, Shanghai, 200433, China
| | - Hao Shen
- Department of Environmental Hygiene, Second Military Medical University, Shanghai, 200433, China
| | - Wenjun Chang
- Department of Environmental Hygiene, Second Military Medical University, Shanghai, 200433, China
| | - Chuanxiang Zhou
- Department of Oral Pathology, Peking University School and Hospital of Stomatology, Beijing, 100081, China.
| | - Yamin Pan
- Department of Digestive Endoscopy, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Yiming Lu
- Department of Biochemical Pharmacy, School of Pharmacy, Second Military Medical University, Shanghai, 200433, China.
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18
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Aberrant neuronal activity-induced signaling and gene expression in a mouse model of RASopathy. PLoS Genet 2017; 13:e1006684. [PMID: 28346493 PMCID: PMC5386306 DOI: 10.1371/journal.pgen.1006684] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Revised: 04/10/2017] [Accepted: 03/13/2017] [Indexed: 12/16/2022] Open
Abstract
Noonan syndrome (NS) is characterized by reduced growth, craniofacial abnormalities, congenital heart defects, and variable cognitive deficits. NS belongs to the RASopathies, genetic conditions linked to mutations in components and regulators of the Ras signaling pathway. Approximately 50% of NS cases are caused by mutations in PTPN11. However, the molecular mechanisms underlying cognitive impairments in NS patients are still poorly understood. Here, we report the generation and characterization of a new conditional mouse strain that expresses the overactive Ptpn11D61Y allele only in the forebrain. Unlike mice with a global expression of this mutation, this strain is viable and without severe systemic phenotype, but shows lower exploratory activity and reduced memory specificity, which is in line with a causal role of disturbed neuronal Ptpn11 signaling in the development of NS-linked cognitive deficits. To explore the underlying mechanisms we investigated the neuronal activity-regulated Ras signaling in brains and neuronal cultures derived from this model. We observed an altered surface expression and trafficking of synaptic glutamate receptors, which are crucial for hippocampal neuronal plasticity. Furthermore, we show that the neuronal activity-induced ERK signaling, as well as the consecutive regulation of gene expression are strongly perturbed. Microarray-based hippocampal gene expression profiling revealed profound differences in the basal state and upon stimulation of neuronal activity. The neuronal activity-dependent gene regulation was strongly attenuated in Ptpn11D61Y neurons. In silico analysis of functional networks revealed changes in the cellular signaling beyond the dysregulation of Ras/MAPK signaling that is nearly exclusively discussed in the context of NS at present. Importantly, changes in PI3K/AKT/mTOR and JAK/STAT signaling were experimentally confirmed. In summary, this study uncovers aberrant neuronal activity-induced signaling and regulation of gene expression in Ptpn11D61Y mice and suggests that these deficits contribute to the pathophysiology of cognitive impairments in NS.
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19
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Intracellular IL-37b interacts with Smad3 to suppress multiple signaling pathways and the metastatic phenotype of tumor cells. Oncogene 2017; 36:2889-2899. [DOI: 10.1038/onc.2016.444] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2016] [Revised: 10/09/2016] [Accepted: 10/23/2016] [Indexed: 12/16/2022]
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20
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Teng JF, Wang K, Li Y, Qu FJ, Yuan Q, Cui XG, Wang QX, Xu DF. Conditional Knockout of Src Homology 2 Domain-containing Protein Tyrosine Phosphatase-2 in Myeloid Cells Attenuates Renal Fibrosis after Unilateral Ureter Obstruction. Chin Med J (Engl) 2016; 128:1196-201. [PMID: 25947403 PMCID: PMC4831547 DOI: 10.4103/0366-6999.156121] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
Background: Src homology 2 domain-containing protein tyrosine phosphatase-2 (SHP-2) is a kind of intracellular protein tyrosine phosphatase. Studies have revealed its roles in various disease, however, whether SHP-2 involves in renal fibrosis remains unclear. The aim of this study was to explore the roles of myeloid cells SHP-2 in renal interstitial fibrosis. Methods: Myeloid cells SHP-2 gene was conditionally knocked-out (CKO) in mice using loxP-Cre system, and renal interstitial fibrosis was induced by unilateral ureter obstruction (UUO). The total collagen deposition in the renal interstitium was assessed using picrosirius red stain. F4/80 immunostaing was used to evaluate macrophage infiltration in renal tubular interstitium. Quantitative real-time polymerase chain reaction and enzyme linked immunosorbent assay were used to analyze the production of cytokines in the kidney. Transferase-mediated dUTP nick-end labeling stain was used to assess the apoptotic renal tubular epithelial cells. Results: Src homology 2 domain-containing protein tyrosine phosphatase-2 gene CKO in myeloid cells significantly reduced collagen deposition in the renal interstitium after UUO. Macrophage infiltration was evidently decreased in renal tubular interstitium of SHP-2 CKO mice. Meanwhile, the production of pro-inflammatory cytokines was significantly suppressed in SHP-2 CKO mice. However, no significant difference was observed in the number of apoptotic renal tubular epithelial cells between wild-type and SHP-2 CKO mice. Conclusions: Our observations suggested that SHP-2 in myeloid cells plays a pivotal role in the pathogenesis of renal fibrosis, and that silencing of SHP-2 gene in myeloid cells may protect renal from inflammatory damage and prevent renal fibrosis after renal injury.
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Affiliation(s)
| | | | | | | | | | | | | | - Dan-Feng Xu
- Department of Urology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
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21
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Karyampudi L, Lamichhane P, Krempski J, Kalli KR, Behrens MD, Vargas DM, Hartmann LC, Janco JMT, Dong H, Hedin KE, Dietz AB, Goode EL, Knutson KL. PD-1 Blunts the Function of Ovarian Tumor-Infiltrating Dendritic Cells by Inactivating NF-κB. Cancer Res 2015; 76:239-50. [PMID: 26567141 DOI: 10.1158/0008-5472.can-15-0748] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Accepted: 10/13/2015] [Indexed: 01/22/2023]
Abstract
The PD-1:PD-L1 immune signaling axis mediates suppression of T-cell-dependent tumor immunity. PD-1 expression was recently found to be upregulated on tumor-infiltrating murine (CD11c(+)CD11b(+)CD8(-)CD209a(+)) and human (CD1c(+)CD19(-)) myeloid dendritic cells (TIDC), an innate immune cell type also implicated in immune escape. However, there is little knowledge concerning how PD-1 regulates innate immune cells. In this study, we examined the role of PD-1 in TIDCs derived from mice bearing ovarian tumors. Similar to lymphocytes, TIDC expression of PD-1 was associated with expression of the adapter protein SHP-2, which signals to NF-κB; however, in contrast to its role in lymphocytes, we found that expression of PD-1 in TIDC tonically paralyzed NF-κB activation. Further mechanistic investigations showed that PD-1 blocked NF-κB-dependent cytokine release in a SHP-2-dependent manner. Conversely, inhibition of NF-κB-mediated antigen presentation by PD-1 occurred independently of SHP-2. Collectively, our findings revealed that PD-1 acts in a distinct manner in innate immune cells compared with adaptive immune cells, prompting further investigations of the signaling pathways controlled by this central mediator of immune escape in cancer.
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Affiliation(s)
| | - Purushottam Lamichhane
- Vaccine and Gene Therapy Institute, Port St. Lucie, Florida. Department of Immunology, Mayo Clinic, Rochester, Minnesota
| | - James Krempski
- Department of Immunology, Mayo Clinic, Rochester, Minnesota
| | | | | | - Doris M Vargas
- Department of Immunology, Mayo Clinic, Rochester, Minnesota
| | | | - Jo Marie T Janco
- Department of Gynecologic Surgery Mayo Clinic, Mayo Clinic, Rochester, Minnesota
| | - Haidong Dong
- Department of Immunology, Mayo Clinic, Rochester, Minnesota
| | - Karen E Hedin
- Department of Immunology, Mayo Clinic, Rochester, Minnesota
| | - Allan B Dietz
- Human Cell Therapy Lab, Mayo Clinic, Rochester, Minnesota
| | - Ellen L Goode
- Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
| | - Keith L Knutson
- Vaccine and Gene Therapy Institute, Port St. Lucie, Florida. Department of Immunology, Mayo Clinic, Rochester, Minnesota.
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Kaneko S, Nakatani Y, Takezaki T, Hide T, Yamashita D, Ohtsu N, Ohnishi T, Terasaka S, Houkin K, Kondo T. Ceacam1L Modulates STAT3 Signaling to Control the Proliferation of Glioblastoma-Initiating Cells. Cancer Res 2015; 75:4224-34. [PMID: 26238781 DOI: 10.1158/0008-5472.can-15-0412] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2015] [Accepted: 06/27/2015] [Indexed: 11/16/2022]
Abstract
Glioblastoma-initiating cells (GIC) are a tumorigenic cell subpopulation resistant to radiotherapy and chemotherapy, and are a likely source of recurrence. However, the basis through which GICs are maintained has yet to be elucidated in detail. We herein demonstrated that the carcinoembryonic antigen-related cell adhesion molecule Ceacam1L acts as a crucial factor in GIC maintenance and tumorigenesis by activating c-Src/STAT3 signaling. Furthermore, we showed that monomers of the cytoplasmic domain of Ceacam1L bound to c-Src and STAT3 and induced their phosphorylation, whereas oligomerization of this domain ablated this function. Our results suggest that Ceacam1L-dependent adhesion between GIC and surrounding cells play an essential role in GIC maintenance and proliferation, as mediated by signals transmitted by monomeric forms of the Ceacam1L cytoplasmic domain.
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Affiliation(s)
- Sadahiro Kaneko
- Division of Stem Cell Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan. Department of Neurosurgery, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
| | - Yuka Nakatani
- Laboratory for Cell Lineage Modulation, Center for Developmental Biology, RIKEN, Kobe, Hyogo, Japan
| | - Tatsuya Takezaki
- Laboratory for Cell Lineage Modulation, Center for Developmental Biology, RIKEN, Kobe, Hyogo, Japan. Department of Neurosurgery, Kumamoto University Graduate School of Medical Science, Kumamoto, Kumamoto, Japan
| | - Takuichiro Hide
- Laboratory for Cell Lineage Modulation, Center for Developmental Biology, RIKEN, Kobe, Hyogo, Japan. Department of Neurosurgery, Kumamoto University Graduate School of Medical Science, Kumamoto, Kumamoto, Japan
| | - Daisuke Yamashita
- Department of Neurosurgery, Ehime University Graduate School of Medicine, To-on, Ehime, Japan
| | - Naoki Ohtsu
- Division of Stem Cell Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Takanori Ohnishi
- Department of Neurosurgery, Ehime University Graduate School of Medicine, To-on, Ehime, Japan
| | - Shunsuke Terasaka
- Department of Neurosurgery, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
| | - Kiyohiro Houkin
- Department of Neurosurgery, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
| | - Toru Kondo
- Division of Stem Cell Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan. Laboratory for Cell Lineage Modulation, Center for Developmental Biology, RIKEN, Kobe, Hyogo, Japan.
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23
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Li XJ, Goodwin CB, Nabinger SC, Richine BM, Yang Z, Hanenberg H, Ohnishi H, Matozaki T, Feng GS, Chan RJ. Protein-tyrosine phosphatase Shp2 positively regulates macrophage oxidative burst. J Biol Chem 2014; 290:3894-909. [PMID: 25538234 DOI: 10.1074/jbc.m114.614057] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Macrophages are vital to innate immunity and express pattern recognition receptors and integrins for the rapid detection of invading pathogens. Stimulation of Dectin-1 and complement receptor 3 (CR3) activates Erk- and Akt-dependent production of reactive oxygen species (ROS). Shp2, a protein-tyrosine phosphatase encoded by Ptpn11, promotes activation of Ras-Erk and PI3K-Akt and is crucial for hematopoietic cell function; however, no studies have examined Shp2 function in particulate-stimulated ROS production. Maximal Dectin-1-stimulated ROS production corresponded kinetically to maximal Shp2 and Erk phosphorylation. Bone marrow-derived macrophages (BMMs) from mice with a conditionally deleted allele of Ptpn11 (Shp2(flox/flox);Mx1Cre+) produced significantly lower ROS levels compared with control BMMs. Although YFP-tagged phosphatase dead Shp2-C463A was strongly recruited to the early phagosome, its expression inhibited Dectin-1- and CR3-stimulated phospho-Erk and ROS levels, placing Shp2 phosphatase function and Erk activation upstream of ROS production. Further, BMMs expressing gain of function Shp2-D61Y or Shp2-E76K and peritoneal exudate macrophages from Shp2D61Y/+;Mx1Cre+ mice produced significantly elevated levels of Dectin-1- and CR3-stimulated ROS, which was reduced by pharmacologic inhibition of Erk. SIRPα (signal regulatory protein α) is a myeloid inhibitory immunoreceptor that requires tyrosine phosphorylation to exert its inhibitory effect. YFP-Shp2C463A-expressing cells have elevated phospho-SIRPα levels and an increased Shp2-SIRPα interaction compared with YFP-WT Shp2-expressing cells. Collectively, these findings indicate that Shp2 phosphatase function positively regulates Dectin-1- and CR3-stimulated ROS production in macrophages by dephosphorylating and thus mitigating the inhibitory function of SIRPα and by promoting Erk activation.
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Affiliation(s)
- Xing Jun Li
- From the Department of Pediatrics, the Herman B Wells Center for Pediatric Research, and
| | - Charles B Goodwin
- the Herman B Wells Center for Pediatric Research, and the Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202
| | - Sarah C Nabinger
- the Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202
| | - Briana M Richine
- the Herman B Wells Center for Pediatric Research, and the Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202
| | - Zhenyun Yang
- West Coast University, Los Angeles, California 91606
| | - Helmut Hanenberg
- From the Department of Pediatrics, the Herman B Wells Center for Pediatric Research, and the Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202, the Department of Otorhinolaryngology and Head/Neck Surgery, Heinrich Heine University, 40225 Düsseldorf, Germany
| | - Hiroshi Ohnishi
- the Gunma University Graduate School of Health Sciences, Maebashi, Gunma 371-8514, Japan
| | - Takashi Matozaki
- the Kobe University Graduate School of Medicine, Chuo-Ku, Kobe 650-0017, Japan, and
| | - Gen-Sheng Feng
- the Department of Pathology, University of California, San Diego, La Jolla, California 92093
| | - Rebecca J Chan
- From the Department of Pediatrics, the Herman B Wells Center for Pediatric Research, and the Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202,
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24
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Lauriol J, Jaffré F, Kontaridis MI. The role of the protein tyrosine phosphatase SHP2 in cardiac development and disease. Semin Cell Dev Biol 2014; 37:73-81. [PMID: 25256404 DOI: 10.1016/j.semcdb.2014.09.013] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2014] [Revised: 09/09/2014] [Accepted: 09/15/2014] [Indexed: 02/06/2023]
Abstract
Congenital heart disease is the most common human developmental disorder, affecting ∼1:100 newborns, and is the primary cause of birth-defect related deaths worldwide. As a major regulator of receptor tyrosine kinase (RTK), cytokine and G-protein coupled receptor signaling, the non-receptor protein tyrosine phosphatase SHP2 plays a critical role in normal cardiac development and function. Indeed, SHP2 participates in a wide variety of cellular functions, including proliferation, survival, differentiation, migration, and cell-cell communication. Moreover, human activating and inactivating mutations of SHP2 are responsible for two related developmental disorders called Noonan and LEOPARD Syndromes, respectively, which are both characterized, in part, by congenital heart defects. Structural, enzymologic, biochemical, and SHP2 mouse model studies have together greatly enriched our knowledge of SHP2 and, as such, have also uncovered the diverse roles for SHP2 in cardiac development, including its contribution to progenitor cell specification, cardiac morphogenesis, and maturation of cardiac valves and myocardial chambers. By delineating the precise mechanisms by which SHP2 is involved in regulating these processes, we can begin to better understand the pathogenesis of cardiac disease and find more strategic and effective therapies for treatment of patients with congenital heart disorders.
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Affiliation(s)
- Jessica Lauriol
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, United States
| | - Fabrice Jaffré
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, United States
| | - Maria I Kontaridis
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, United States; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, United States.
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25
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Marcos-Ramiro B, García-Weber D, Millán J. TNF-induced endothelial barrier disruption: beyond actin and Rho. Thromb Haemost 2014; 112:1088-102. [PMID: 25078148 DOI: 10.1160/th14-04-0299] [Citation(s) in RCA: 119] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2014] [Accepted: 06/16/2014] [Indexed: 11/05/2022]
Abstract
The decrease of endothelial barrier function is central to the long-term inflammatory response. A pathological alteration of the ability of endothelial cells to modulate the passage of cells and solutes across the vessel underlies the development of inflammatory diseases such as atherosclerosis and multiple sclerosis. The inflammatory cytokine tumour necrosis factor (TNF) mediates changes in the barrier properties of the endothelium. TNF activates different Rho GTPases, increases filamentous actin and remodels endothelial cell morphology. However, inhibition of actin-mediated remodelling is insufficient to prevent endothelial barrier disruption in response to TNF, suggesting that additional molecular mechanisms are involved. Here we discuss, first, the pivotal role of Rac-mediated generation of reactive oxygen species (ROS) to regulate the integrity of endothelial cell-cell junctions and, second, the ability of endothelial adhesion receptors such as ICAM-1, VCAM-1 and PECAM-1, involved in leukocyte transendothelial migration, to control endothelial permeability to small molecules, often through ROS generation. These adhesion receptors regulate endothelial barrier function in ways both dependent on and independent of their engagement by immune cells, and orchestrate the crosstalk between leukocyte transendothelial migration and endothelial permeability during inflammation.
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Affiliation(s)
| | | | - J Millán
- Jaime Millán, Centro de Biología Molecular Severo Ochoa, C/ Nicolás Cabrera 1, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain, Tel.: +34 911964713, Fax: +34 911964420, E-mail:
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26
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Negm OH, Mannsperger HA, McDermott EM, Drewe E, Powell RJ, Todd I, Fairclough LC, Tighe PJ. A pro-inflammatory signalome is constitutively activated by C33Y mutant TNF receptor 1 in TNF receptor-associated periodic syndrome (TRAPS). Eur J Immunol 2014; 44:2096-110. [PMID: 24668260 PMCID: PMC4285816 DOI: 10.1002/eji.201344328] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2013] [Revised: 02/09/2014] [Accepted: 03/21/2014] [Indexed: 12/20/2022]
Abstract
Mutations in TNFRSF1A encoding TNF receptor 1 (TNFR1) cause the autosomal dominant TNF receptor-associated periodic syndrome (TRAPS): a systemic autoinflammatory disorder. Misfolding, intracellular aggregation, and ligand-independent signaling by mutant TNFR1 are central to disease pathophysiology. Our aim was to understand the extent of signaling pathway perturbation in TRAPS. A prototypic mutant TNFR1 (C33Y), and wild-type TNFR1 (WT), were expressed at near physiological levels in an SK-Hep-1 cell model. TNFR1-associated signaling pathway intermediates were examined in this model, and in PBMCs from C33Y TRAPS patients and healthy controls. In C33Y-TNFR1-expressing SK-Hep-1 cells and TRAPS patients’ PBMCs, a subtle, constitutive upregulation of a wide spectrum of signaling intermediates and their phosphorylated forms was observed; these were associated with a proinflammatory/antiapoptotic phenotype. In TRAPS patients’ PBMCs, this upregulation of proinflammatory signaling pathways was observed irrespective of concurrent treatment with glucocorticoids, anakinra or etanercept, and the absence of overt clinical symptoms at the time that the blood samples were taken. This study reveals the pleiotropic effect of a TRAPS-associated mutant form of TNFR1 on inflammatory signaling pathways (a proinflammatory signalome), which is consistent with the variable and limited efficacy of cytokine-blocking therapies in TRAPS. It highlights new potential target pathways for therapeutic intervention.
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Affiliation(s)
- Ola H Negm
- School of Life Sciences, The University of Nottingham, UK; Medical Microbiology and Immunology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
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27
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Hu M, Yin H, Mitra MS, Liang X, Ajmo JM, Nadra K, Chrast R, Finck BN, You M. Hepatic-specific lipin-1 deficiency exacerbates experimental alcohol-induced steatohepatitis in mice. Hepatology 2013; 58:1953-63. [PMID: 23787969 PMCID: PMC3835749 DOI: 10.1002/hep.26589] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2013] [Accepted: 06/12/2013] [Indexed: 12/22/2022]
Abstract
UNLABELLED Lipin-1 regulates lipid metabolism by way of its function as an enzyme in the triglyceride synthesis pathway and as a transcriptional coregulatory protein and is highly up-regulated in alcoholic fatty liver disease. In the present study, using a liver-specific lipin-1-deficient (lipin-1LKO) mouse model, we aimed to investigate the functional role of lipin-1 in the development of alcoholic steatohepatitis and explore the underlying mechanisms. Alcoholic liver injury was achieved by pair feeding wild-type and lipin-1LKO mice with modified Lieber-DeCarli ethanol-containing low-fat diets for 4 weeks. Surprisingly, chronically ethanol-fed lipin-1LKO mice showed markedly greater hepatic triglyceride and cholesterol accumulation, and augmented elevation of serum liver enzymes accompanied by increased hepatic proinflammatory cytokine expression. Our studies further revealed that hepatic removal of lipin-1 in mice augmented ethanol-induced impairment of hepatic fatty acid oxidation and lipoprotein production, likely by way of deactivation of peroxisome proliferator-activated receptor γ coactivator-1 alpha, a prominent transcriptional regulator of lipid metabolism. CONCLUSIONS Liver-specific lipin-1 deficiency in mice exacerbates the development and progression of experimental alcohol-induced steatohepatitis. Pharmacological or nutritional modulation of hepatic lipin-1 may be beneficial for the prevention or treatment of human alcoholic fatty liver disease.
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Affiliation(s)
- Ming Hu
- Department of Molecular Pharmacology and Physiology, University of South Florida Health Sciences Center, 12901 Bruce B. Downs Blvd. Tampa, FL 33612, USA
| | - Huquan Yin
- Department of Molecular Pharmacology and Physiology, University of South Florida Health Sciences Center, 12901 Bruce B. Downs Blvd. Tampa, FL 33612, USA
| | - Mayurranjan S. Mitra
- Department of Medicine, Washington University School of Medicine, St.Louis, MO 63110, USA
| | - Xiaomei Liang
- Department of Molecular Pharmacology and Physiology, University of South Florida Health Sciences Center, 12901 Bruce B. Downs Blvd. Tampa, FL 33612, USA
| | - Joanne M. Ajmo
- Department of Molecular Pharmacology and Physiology, University of South Florida Health Sciences Center, 12901 Bruce B. Downs Blvd. Tampa, FL 33612, USA
| | - Karim Nadra
- Department of Medical Genetics, University of Lausanne, 1005 Lausanne, Switzerland
| | - Roman Chrast
- Department of Medical Genetics, University of Lausanne, 1005 Lausanne, Switzerland
| | - Brian N. Finck
- Department of Medicine, Washington University School of Medicine, St.Louis, MO 63110, USA
| | - Min You
- Department of Molecular Pharmacology and Physiology, University of South Florida Health Sciences Center, 12901 Bruce B. Downs Blvd. Tampa, FL 33612, USA
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Xie H, Huang S, Li W, Zhao H, Zhang T, Zhang D. Upregulation of Src homology phosphotyrosyl phosphatase 2 (Shp2) expression in oral cancer and knockdown of Shp2 expression inhibit tumor cell viability and invasion in vitro. Oral Surg Oral Med Oral Pathol Oral Radiol 2013; 117:234-42. [PMID: 24439919 DOI: 10.1016/j.oooo.2013.10.018] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2013] [Revised: 10/21/2013] [Accepted: 10/24/2013] [Indexed: 01/05/2023]
Abstract
OBJECTIVE This study investigated the clinical significance of Shp2 protein expression in oral squamous cell carcinoma (OSCC) and elucidated its biologic significance in OSCC cells. STUDY DESIGN A total of 88 OSCC cases were used to assess Shp2 expression, out of which 70 were for immunohistochemistry and 18 paired tumors vs normal tissues were for Western blot of Shp2 expression. OSCC cells were used to assess the effects of Shp2 knockdown for cell viability, apoptosis, invasion, and protein expressions. RESULTS Expression of Shp2 protein was significantly upregulated in OSCC tissues compared with the normal tissues, and Shp2 overexpression was associated with advanced tumor clinical stages and lymph node metastasis ex vivo. Knockdown of Shp2 expression in vitro inhibited OSCC cell viability and invasion but induced apoptosis by regulating expression of the apoptosis-related proteins. CONCLUSIONS The data indicated that Shp2 may play an important role in OSCC progression. Further studies will investigate whether a target of Shp2 expression could be a novel therapeutic strategy for clinical control of OSCC.
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Affiliation(s)
- Hongjun Xie
- Department of Oral & Maxillofacial Surgery, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China
| | - Shengyun Huang
- Department of Oral & Maxillofacial Surgery, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China
| | - Wengang Li
- Department of Oral & Maxillofacial Surgery, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China
| | - Hongbo Zhao
- Department of Oral & Maxillofacial Surgery, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China
| | - Tianqi Zhang
- Department of Oral & Maxillofacial Surgery, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China
| | - Dongsheng Zhang
- Department of Oral & Maxillofacial Surgery, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China.
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Pan YF, Dong LW, Wang M, Yang GZ, Zhang J, Li SX, Zhang B, Yang C, Li Z, Tan YX, Wang HY. Signal regulatory protein α negatively regulates mast-cell activation following FcεRI aggregation. Eur J Immunol 2013; 43:1598-607. [DOI: 10.1002/eji.201243031] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2012] [Revised: 01/31/2013] [Accepted: 03/08/2013] [Indexed: 12/13/2022]
Affiliation(s)
- Yu-fei Pan
- International Cooperation Laboratory on Signal Transduction; Eastern Hepatobiliary Surgery Institute, the Second Military Medical University; Shanghai; P. R. China
| | - Li-wei Dong
- International Cooperation Laboratory on Signal Transduction; Eastern Hepatobiliary Surgery Institute, the Second Military Medical University; Shanghai; P. R. China
| | - Min Wang
- International Cooperation Laboratory on Signal Transduction; Eastern Hepatobiliary Surgery Institute, the Second Military Medical University; Shanghai; P. R. China
| | - Guang-zhen Yang
- International Cooperation Laboratory on Signal Transduction; Eastern Hepatobiliary Surgery Institute, the Second Military Medical University; Shanghai; P. R. China
| | - Jian Zhang
- International Cooperation Laboratory on Signal Transduction; Eastern Hepatobiliary Surgery Institute, the Second Military Medical University; Shanghai; P. R. China
| | - Shuang-xi Li
- International Cooperation Laboratory on Signal Transduction; Eastern Hepatobiliary Surgery Institute, the Second Military Medical University; Shanghai; P. R. China
| | - Bo Zhang
- International Cooperation Laboratory on Signal Transduction; Eastern Hepatobiliary Surgery Institute, the Second Military Medical University; Shanghai; P. R. China
| | - Chun Yang
- International Cooperation Laboratory on Signal Transduction; Eastern Hepatobiliary Surgery Institute, the Second Military Medical University; Shanghai; P. R. China
| | - Zhong Li
- International Cooperation Laboratory on Signal Transduction; Eastern Hepatobiliary Surgery Institute, the Second Military Medical University; Shanghai; P. R. China
| | - Ye-xiong Tan
- International Cooperation Laboratory on Signal Transduction; Eastern Hepatobiliary Surgery Institute, the Second Military Medical University; Shanghai; P. R. China
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Epithelial tyrosine phosphatase SHP-2 protects against intestinal inflammation in mice. Mol Cell Biol 2013; 33:2275-84. [PMID: 23530062 DOI: 10.1128/mcb.00043-13] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Polymorphisms of PTPN11 encoding SHP-2 are biomarkers for ulcerative colitis (UC) susceptibility. However, their functional relevance is unknown. We thus investigated the role of epithelial SHP-2 in the control of intestinal homeostasis. Mice with an intestinal epithelial cell-specific SHP-2 deletion (SHP-2(IEC-KO) mice) were generated. Control and SHP-2(IEC-KO) mice were monitored for clinical symptoms and sacrificed for histological staining and Western blot analyses. Cytokines and chemokines, as well as intestinal permeability, were quantified. SHP-2 mRNA expression was evaluated in control and UC patients. SHP-2(IEC-KO) mice showed growth retardation compared to control littermates and rapidly developed severe colitis. Colon architecture was markedly altered with infiltration of immune cells, crypt abscesses, neutrophil accumulation, and reduced goblet cell numbers. Decreased expression of claudins was associated with enhanced intestinal permeability in mutant SHP-2(IEC-KO) mice. Inflammatory transcription factors Stat3 and NF-κB were hyperactivated early in the mutant colonic epithelium. Levels of several epithelial chemokines and cytokines were markedly enhanced in SHP-2(IEC-KO) mice. Of note, antibiotic treatment remarkably impaired the development of colitis in SHP-2(IEC-KO) mice. Finally, SHP-2 mRNA levels were significantly reduced in intestinal biopsy specimens from UC patients. Our results establish intestinal epithelial SHP-2 as a critical determinant for prevention of gut inflammation.
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Sanchez-Correa B, Bergua JM, Campos C, Gayoso I, Arcos MJ, Bañas H, Morgado S, Casado JG, Solana R, Tarazona R. Cytokine profiles in acute myeloid leukemia patients at diagnosis: Survival is inversely correlated with IL-6 and directly correlated with IL-10 levels. Cytokine 2013; 61:885-91. [DOI: 10.1016/j.cyto.2012.12.023] [Citation(s) in RCA: 109] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2012] [Revised: 12/19/2012] [Accepted: 12/22/2012] [Indexed: 11/27/2022]
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Jiang J, Jin MS, Kong F, Wang YP, Jia ZF, Cao DH, Ma HX, Suo J, Cao XY. Increased expression of tyrosine phosphatase SHP-2 in Helicobacter pylori-infected gastric cancer. World J Gastroenterol 2013; 19:575-80. [PMID: 23382639 PMCID: PMC3558584 DOI: 10.3748/wjg.v19.i4.575] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2012] [Revised: 11/17/2012] [Accepted: 12/15/2012] [Indexed: 02/06/2023] Open
Abstract
AIM To explore the alteration of tyrosine phosphatase SHP-2 protein expression in gastric cancer and to assess its prognostic values. METHODS Three hundred and five consecutive cases of gastric cancer were enrolled into this study. SHP-2 expression was carried out in 305 gastric cancer specimens, of which 83 were paired adjacent normal gastric mucus samples, using a tissue microarray immunohistochemical method. Correlations were analyzed between expression levels of SHP-2 protein and tumor parameters or clinical outcomes. Serum anti-Helicobacter pylori (H. pylori) immunoglobulin G was detected with enzyme-linked immunosorbent assay. Cox proportional hazards model was used to evaluate prognostic values by compassion of the expression levels of SHP-2 and disease-specific survivals in patients. RESULTS SHP-2 staining was found diffuse mainly in the cytoplasm and the weak staining was also observed in the nucleus in gastric mucosa cells. Thirty-two point five percent of normal epithelial specimen and 62.6% of gastric cancer specimen were identified to stain with SHP-2 antibody positively (P < 0.001). Though SHP-2 staining intensities were stronger in the H. pylori (+) group than in the H. pylori (-) group, no statistically significant difference was found in the expression levels of SHP-2 between H. pylori (+) and H. pylori (-) gastric cancer (P = 0.40). The SHP-2 expression in gastric cancer was not significantly associated with cancer stages, lymph node metastases, and distant metastasis of the tumors (P = 0.34, P = 0.17, P = 0.52). Multivariate analysis demonstrated no correlation between SHP-2 expression and disease-free survival (P = 0.86). CONCLUSION Increased expression of SHP-2 protein in gastric cancer specimen suggesting the aberrant up-regulation of SHP-2 protein might play an important role in the gastric carcinogenesis.
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Nagata N, Matsuo K, Bettaieb A, Bakke J, Matsuo I, Graham J, Xi Y, Liu S, Tomilov A, Tomilova N, Gray S, Jung DY, Ramsey JJ, Kim JK, Cortopassi G, Havel PJ, Haj FG. Hepatic Src homology phosphatase 2 regulates energy balance in mice. Endocrinology 2012; 153:3158-69. [PMID: 22619361 PMCID: PMC3380313 DOI: 10.1210/en.2012-1406] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The Src homology 2 domain-containing protein-tyrosine phosphatase Src homology phosphatase 2 (Shp2) is a negative regulator of hepatic insulin action in mice fed regular chow. To investigate the role of hepatic Shp2 in lipid metabolism and energy balance, we determined the metabolic effects of its deletion in mice challenged with a high-fat diet (HFD). We analyzed body mass, lipid metabolism, insulin sensitivity, and glucose tolerance in liver-specific Shp2-deficient mice (referred to herein as LSHKO) and control mice fed HFD. Hepatic Shp2 protein expression is regulated by nutritional status, increasing in mice fed HFD and decreasing during fasting. LSHKO mice gained less weight and exhibited increased energy expenditure compared with control mice. In addition, hepatic Shp2 deficiency led to decreased liver steatosis, enhanced insulin-induced suppression of hepatic glucose production, and impeded the development of insulin resistance after high-fat feeding. At the molecular level, LSHKO exhibited decreased hepatic endoplasmic reticulum stress and inflammation compared with control mice. In addition, tyrosine and serine phosphorylation of total and mitochondrial signal transducer and activator of transcription 3 were enhanced in LSHKO compared with control mice. In line with this observation and the increased energy expenditure of LSHKO, oxygen consumption rate was higher in liver mitochondria of LSHKO compared with controls. Collectively, these studies identify hepatic Shp2 as a novel regulator of systemic energy balance under conditions of high-fat feeding.
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Affiliation(s)
- Naoto Nagata
- Department of Nutrition, University of California Davis, Davis, California 95616, USA
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Meng F, Zhao X, Zhang S. Expression and significance of SHP-2 in human papillomavirus infected cervical cancer. ACTA ACUST UNITED AC 2012; 32:247-251. [PMID: 22528229 DOI: 10.1007/s11596-012-0044-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2011] [Indexed: 01/27/2023]
Abstract
This study investigated the expression and prognostic value of SHP-2 in cervical cancer caused by human papillomavirus (HPV) infection. Forty-five specimens from patients with cervical cancer (stage I-III), 32 specimens from patients with cervical intraepithelial neoplasia (CIN) (I, II) and 20 normal cervical samples from patients with hysteromyoma were collected in Department of Pathology for comparison. The expression levels of SHP-2 and IFN-β proteins were detected by using immunohistochemistry. The mRNA expression level of SHP-2 was detected by using quantitative real-time polymerase chain reaction (PCR). HPVs were detected by HPV GenoArray Test. The Spearman correlation was used to compare the expression level of SHP-2 in HPV infected cervical cancer vs non-HPV infected normal cervix. The level of SHP-2 protein expression in the cancer tissues (88.8%) was significantly higher than in CIN tissues (62.5%) and normal cervixes (45%) (P<0.05 and P<0.05, respectively). The SHP-2 mRNA levels in the cancer tissues were upregulated as compared with those in the normal cervixes (P<0.05). Twenty-one (46.7%) cervical cancers, 25 (78.1%) CINs and 17 (85%) normal cervixes showed IFN-β positive staining in cytoplasm. There was statistically significant difference in the expression rate of IFN-β between cervical cancer and normal cervix (χ (2)=8.378, P<0.05) as well as between cervical cancer and CIN (χ (2)=7.695, P<0.05). HPV16/18 infections could be found in normal cervixs (15%), CINs (68.7%) and cervical cancers (84.4%). There was a correlation between HPV infection and SHP-2 expression in cervical cancer (r (s)=0.653, P<0.05). SHP-2 may be a useful prognostic and diagnostic indicator for HPV infected cervical cancer. In cervical cancers, SHP-2 mRNA and protein overexpression was associated with IFN-β lower-expression.
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Affiliation(s)
- Fei Meng
- Department of Obstetrics and Gynecology, Shengjing Hospital, China Medical University, Shenyang, 110004, China
| | - Xiaoyun Zhao
- Department of Microbiology and Cell Biology, Shenyang Pharmaceutical University School of Life Science and Biopharmaceutics, Shenyang, 110016, China
| | - Shulan Zhang
- Department of Obstetrics and Gynecology, Shengjing Hospital, China Medical University, Shenyang, 110004, China.
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Bettaieb A, Matsuo K, Matsuo I, Nagata N, Chahed S, Liu S, Haj FG. Adipose-specific deletion of Src homology phosphatase 2 does not significantly alter systemic glucose homeostasis. Metabolism 2011; 60:1193-201. [PMID: 21353259 PMCID: PMC4433310 DOI: 10.1016/j.metabol.2011.01.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2010] [Revised: 12/21/2010] [Accepted: 01/12/2011] [Indexed: 10/18/2022]
Abstract
The SH2 domain-containing protein-tyrosine phosphatase Src homology phosphatase 2 (Shp2) has been implicated in a variety of growth factor signaling pathways, but its metabolic role in some peripheral insulin-responsive tissues remains unknown. To address the metabolic function of Shp2 in adipose tissue, we generated mice with adipose-specific Shp2 deletion using adiponectin-Cre transgenic mice. We then analyzed insulin sensitivity, glucose tolerance, and body mass in adipose-specific Shp2-deficient and control mice on regular chow and high-fat diet (HFD). Control mice on HFD exhibited increased Shp2 expression in various adipose depots compared with those on regular chow. Adiponectin-Cre mice enabled efficient and specific deletion of Shp2 in adipose tissue. However, adipose Shp2 deletion did not significantly alter body mass in mice on chow or HFD. In addition, mice with adipose Shp2 deletion exhibited comparable insulin sensitivity and glucose tolerance compared with controls. Consistent with this, basal and insulin-stimulated Erk and Akt phosphorylations were comparable in adipose tissue of Shp2-deficient and control mice. Our findings indicate that adipose-specific Shp2 deletion does not significantly alter systemic insulin sensitivity and glucose homeostasis.
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Affiliation(s)
- Ahmed Bettaieb
- University of California Davis, Nutrition Department, Davis, CA 95616
| | - Kosuke Matsuo
- University of California Davis, Nutrition Department, Davis, CA 95616
| | - Izumi Matsuo
- University of California Davis, Nutrition Department, Davis, CA 95616
| | - Naoto Nagata
- University of California Davis, Nutrition Department, Davis, CA 95616
| | - Samah Chahed
- University of California Davis, Nutrition Department, Davis, CA 95616
| | - Siming Liu
- University of California Davis, Nutrition Department, Davis, CA 95616
| | - Fawaz G. Haj
- University of California Davis, Nutrition Department, Davis, CA 95616
- Corresponding author: University of California Davis, 3135 Meyer Hall, Davis, CA 95616, Fax: (530) 753-8966, Tel: (530) 752-3214,
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Balasubramanian S, Fan M, Messmer-Blust AF, Yang CH, Trendel JA, Jeyaratnam JA, Pfeffer LM, Vestal DJ. The interferon-gamma-induced GTPase, mGBP-2, inhibits tumor necrosis factor alpha (TNF-alpha) induction of matrix metalloproteinase-9 (MMP-9) by inhibiting NF-kappaB and Rac protein. J Biol Chem 2011; 286:20054-64. [PMID: 21502320 PMCID: PMC3103378 DOI: 10.1074/jbc.m111.249326] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2011] [Revised: 04/15/2011] [Indexed: 11/06/2022] Open
Abstract
Matrix metalloproteinase-9 (MMP-9) is important in numerous normal and pathological processes, including the angiogenic switch during tumor development and tumor metastasis. Whereas TNF-α and other cytokines up-regulate MMP-9 expression, interferons (IFNs) inhibit MMP-9 expression. We found that IFN-γ treatment or forced expression of the IFN-induced GTPase, mGBP-2, inhibit TNF-α-induced MMP-9 expression in NIH 3T3 fibroblasts, by inhibiting MMP-9 transcription. The NF-κB transcription factor is required for full induction of MMP-9 by TNF-α. Both IFN-γ and mGBP-2 inhibit the transcription of a NF-κB-dependent reporter construct, suggesting that mGBP-2 inhibits MMP-9 induction via inhibition of NF-κB-mediated transcription. Interestingly, mGBP-2 does not inhibit TNF-α-induced degradation of IκBα or p65/RelA translocation into the nucleus. However, mGBP-2 inhibits p65 binding to a κB oligonucleotide probe in gel shift assays and to the MMP-9 promoter in chromatin immunoprecipitation assays. In addition, TNF-α activation of NF-κB in NIH 3T3 cells is dependent on Rac activation, as evidenced by the inhibition of TNF-α induction of NF-κB-mediated transcription by a dominant inhibitory form of Rac1. A role for Rac in the inhibitory action of mGBP-2 on NF-κB is further shown by the findings that mGBP-2 inhibits TNF-α activation of endogenous Rac and constitutively activate Rac can restore NF-κB transcription in the presence of mGBP-2. This is a novel mechanism by which IFNs can inhibit the cytokine induction of MMP-9 expression.
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Affiliation(s)
- Sujata Balasubramanian
- From the Department of Biological Sciences, University of Toledo, Toledo, Ohio 43606 and
| | - Meiyun Fan
- the Department of Pathology, University of Tennessee Health Science Center, Memphis, Tennessee 38163
| | | | - Chuan H. Yang
- the Department of Pathology, University of Tennessee Health Science Center, Memphis, Tennessee 38163
| | - Jill A. Trendel
- From the Department of Biological Sciences, University of Toledo, Toledo, Ohio 43606 and
| | - Jonathan A. Jeyaratnam
- From the Department of Biological Sciences, University of Toledo, Toledo, Ohio 43606 and
| | - Lawrence M. Pfeffer
- the Department of Pathology, University of Tennessee Health Science Center, Memphis, Tennessee 38163
| | - Deborah J. Vestal
- From the Department of Biological Sciences, University of Toledo, Toledo, Ohio 43606 and
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Rego D, Kumar A, Nilchi L, Wright K, Huang S, Kozlowski M. IL-6 Production Is Positively Regulated by Two DistinctSrcHomology Domain 2-Containing Tyrosine Phosphatase-1 (SHP-1)–Dependent CCAAT/Enhancer-Binding Protein β and NF-κB Pathways and an SHP-1–Independent NF-κB Pathway in Lipopolysaccharide-Stimulated Bone Marrow-Derived Macrophages. THE JOURNAL OF IMMUNOLOGY 2011; 186:5443-56. [DOI: 10.4049/jimmunol.1003551] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
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Ardalan MR, Ghabili K, Pourabbas R, Shoja MM. A causative link between periodontal disease and glomerulonephritis: a preliminary study. Ther Clin Risk Manag 2011; 7:93-8. [PMID: 21445283 PMCID: PMC3061848 DOI: 10.2147/tcrm.s14106] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2011] [Indexed: 12/11/2022] Open
Abstract
Background: Periodontal disease has been associated with a number of systemic diseases. A high prevalence of periodontitis among individuals with chronic kidney diseases and end-stage renal disease has been reported. However, no association between periodontal diseases and glomerulonephritis has previously been investigated. Objective: The aim of this study was to assess the severity and possible role of periodontitis in a group of patients with unknown primary glomerulonephritis. Methods: Ten patients with unknown primary glomerulonephritis, and who had a renal biopsy with stable renal function and serum creatinine <1.6 mg/dL, were recruited. Severity of the periodontal disease was clinically measured with plaque index (PI), gingival index (GI), and periodontal pocket depth (PD). The subjects received appropriate dental treatments where indicated. The patients were also put on angiotensin-converting enzyme inhibitor or angiotensin receptor blockers for controlling blood pressure and proteinuria. Six months following appropriate periodontal treatment, renal function, degree of proteinuria, and level of C-reactive protein (CRP) were measured in each individual. Results: The median age of the patients was 30 (15.8) years. The median urine protein excretion was lower following the periodontal therapy (P=008). Prior to the dental and/or periodontal therapies, the median PI, PD, and GI were 57.5%, 4.3, and 1.1, respectively. The majority of the patients had advanced periodontal disease. In four patients, +2/+3 CRP turned negative after periodontal treatment. Conclusions: The present study revealed that a causative link might exist between periodontal disease and glomerulonephritis.
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Steevels TAM, Meyaard L. Immune inhibitory receptors: essential regulators of phagocyte function. Eur J Immunol 2011; 41:575-87. [PMID: 21312193 DOI: 10.1002/eji.201041179] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2010] [Revised: 01/06/2011] [Accepted: 01/20/2011] [Indexed: 01/21/2023]
Abstract
Phagocytes, including neutrophils, monocytes, and macrophages, play a crucial role in host defense by recognition and elimination of invading pathogens. Phagocytic cells produce reactive oxygen species (ROS), inflammatory cytokines, and chemokines, leading to bacterial killing and to recruitment and activation of additional immune cells. However, inflammatory mediators are potentially harmful for the host and their production is therefore tightly controlled by multiple regulatory mechanisms. One such mechanism is immune suppression by immune inhibitory receptors, which are increasingly acknowledged as potent regulators of the immune response. So far, research has focused on the role of these receptors in the regulation of NK cells, B cells, and T cells. Importantly, an accumulating number of inhibitory receptors have been identified on phagocytes. Here, we review the role of inhibitory receptors in the regulation of phagocyte cytokine production, migration, apoptosis, ROS production, and phagocytosis. Furthermore, we discuss the intracellular mechanisms utilized by distinct inhibitory receptors to regulate specific phagocyte functions. We demonstrate that inhibitory receptors are important regulators of the immune response, which bacteria can use to their advantage.
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Affiliation(s)
- Tessa A M Steevels
- Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
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40
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Kanazawa Y, Saito Y, Supriatna Y, Tezuka H, Kotani T, Murata Y, Okazawa H, Ohnishi H, Kinouchi Y, Nojima Y, Ohteki T, Shimosegawa T, Matozaki T. Role of SIRPα in regulation of mucosal immunity in the intestine. Genes Cells 2010; 15:1189-200. [PMID: 21040253 DOI: 10.1111/j.1365-2443.2010.01453.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Mononuclear phagocytes such as dendritic cells (DCs) and macrophages in the lamina propria (LP) are thought to be important for both induction of inflammatory responses and maintenance of immunologic tolerance in the mammalian intestine. The molecular mechanisms by which these cells regulate intestinal immunity have remained poorly understood, however. Signal regulatory protein α (SIRPα) is a transmembrane protein that is specifically expressed in DCs, macrophages and neutrophils. Here, we show that SIRPα is abundant in CD11c(+) CD11b(+) LP cells of the mouse intestine. Whereas SIRPα did not appear to be important for the steady-state homeostasis of mucosal immunity in the intestine, the flagellin-stimulated production of IL-17 or interferon (IFN)-γ by LP cells of SIRPα mutant (MT) mice that lack the cytoplasmic region of the protein was markedly decreased compared with that observed with wild-type cells. Moreover, the flagellin-induced production of IL-6 by LP cells from SIRPα MT mice was also greatly reduced. SIRPα MT mice were also resistant to the development of colitis induced by IL-10 deficiency. Our data thus suggest that SIRPα expressed on CD11c(+) LP cells is important for the production of IL-17 or IFN-γ in the LP as well as for the development of colitis induced by IL-10 deficiency.
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Affiliation(s)
- Yoshitake Kanazawa
- Laboratory of Biosignal Sciences, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-Machi, Maebashi, Gunma 371-8512, Japan
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An additional long-term mechanism of NF-κB regulation after cytokine treatment in a human hepatoma cell line. Virchows Arch 2010; 457:585-95. [PMID: 20862591 DOI: 10.1007/s00428-010-0970-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2010] [Revised: 08/26/2010] [Accepted: 08/27/2010] [Indexed: 10/19/2022]
Abstract
The eukaryotic transcription factor nuclear factor-κB (NF-κB) is mainly involved in the regulation of immune response and inflammation. A prolonged activation of NF-κB has been reported in context with chronic diseases. What leads to a prolongation of NF-κB activity is not well understood. Here, an increase in total intracellular NF-κB protein and mRNA levels as well as a temporary colocalization of NF-κB with proteasomes in human hepatocytes after treatment with TNF-α or IL-1β is reported. This indicates that beside an instantaneous activation of NF-κB and partly autoregulated inactivation by breakdown and synthesis of the inhibitors of NF-κB (IκBs), there are also mechanisms for a long-term regulation by de novo-synthesis and degradation of NF-κB protein.
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Matsuo K, Delibegovic M, Matsuo I, Nagata N, Liu S, Bettaieb A, Xi Y, Araki K, Yang W, Kahn BB, Neel BG, Haj FG. Altered glucose homeostasis in mice with liver-specific deletion of Src homology phosphatase 2. J Biol Chem 2010; 285:39750-8. [PMID: 20841350 DOI: 10.1074/jbc.m110.153734] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The Src homology 2 domain-containing protein-tyrosine phosphatase Shp2 has been implicated in a variety of growth factor signaling pathways, but its role in insulin signaling has remained unresolved. In vitro studies suggest that Shp2 is both a negative and positive regulator of insulin signaling, although its physiological function in a number of peripheral insulin-responsive tissues remains unknown. To address the metabolic role of Shp2 in the liver, we generated mice with either chronic or acute hepatic Shp2 deletion using tissue-specific Cre-LoxP and adenoviral Cre approaches, respectively. We then analyzed insulin sensitivity, glucose tolerance, and insulin signaling in liver-specific Shp2-deficient and control mice. Mice with chronic Shp2 deletion exhibited improved insulin sensitivity and increased glucose tolerance compared with controls. Acute Shp2 deletion yielded comparable results, indicating that the observed metabolic effects are directly caused by the lack of Shp2 in the liver. These findings correlated with, and were most likely caused by, direct dephosphorylation of insulin receptor substrate (IRS)1/2 in the liver, accompanied by increased PI3K/Akt signaling. In contrast, insulin-induced ERK activation was dramatically attenuated, yet there was no effect on the putative ERK site on IRS1 (Ser(612)) or on S6 kinase 1 activity. These studies show that Shp2 is a negative regulator of hepatic insulin action, and its deletion enhances the activation of PI3K/Akt pathway downstream of the insulin receptor.
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Affiliation(s)
- Kosuke Matsuo
- Department of Nutrition, University of California, Davis, California 95616, USA
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Abstract
The molecular basis for regulation of dendritic cell (DC) development and homeostasis remains unclear. Signal regulatory protein α (SIRPα), an immunoglobulin superfamily protein that is predominantly expressed in DCs, mediates cell-cell signaling by interacting with CD47, another immunoglobulin superfamily protein. We now show that the number of CD11c(high) DCs (conventional DCs, or cDCs), in particular, that of CD8-CD4+ (CD4+) cDCs, is selectively reduced in secondary lymphoid tissues of mice expressing a mutant form of SIRPα that lacks the cytoplasmic region. We also found that SIRPα is required intrinsically within cDCs or DC precursors for the homeostasis of splenic CD4+ cDCs. Differentiation of bone marrow cells from SIRPα mutant mice into DCs induced by either macrophage-granulocyte colony-stimulating factor or Flt3 ligand in vitro was not impaired. Although the accumulation of the immediate precursors of cDCs in the spleen was also not impaired, the half-life of newly generated splenic CD4+ cDCs was markedly reduced in SIRPα mutant mice. Both hematopoietic and nonhematopoietic CD47 was found to be required for the homeostasis of CD4+ cDCs and CD8-CD4- (double negative) cDCs in the spleen. SIRPα as well as its ligand, CD47, are thus important for the homeostasis of CD4+ cDCs or double negative cDCs in lymphoid tissues.
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Abstract
Deregulation of signaling pathways, through mutation or other molecular changes, can ultimately result in disease. The tyrosine phosphatase Shp2 has emerged as a major regulator of receptor tyrosine kinase (RTK) and cytokine receptor signaling. In the last decade, germline mutations in the human PTPN11 gene, encoding Shp2, were linked to Noonan (NS) and LEOPARD syndromes, two multisymptomatic developmental disorders that are characterized by short stature, craniofacial defects, cardiac defects, and mental retardation. Somatic Shp2 mutations are also associated with several types of human malignancies, such as the most common juvenile leukemia, juvenile myelomonocytic leukemia (JMML). Whereas NS and JMML are caused by gain-of-function (GOF) mutations of Shp2, loss-of-function (LOF) mutations are thought to be associated with LEOPARD syndrome. Animal models that carry conditional LOF and GOF mutations have allowed a better understanding of the mechanism of Shp2 function in disease, and shed light on the role of Shp2 in signaling pathways that control decisive events during embryonic development or during cellular transformation/tumorigenesis.
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Zheng Y, An H, Yao M, Hou J, Yu Y, Feng G, Cao X. Scaffolding adaptor protein Gab1 is required for TLR3/4- and RIG-I-mediated production of proinflammatory cytokines and type I IFN in macrophages. THE JOURNAL OF IMMUNOLOGY 2010; 184:6447-56. [PMID: 20435932 DOI: 10.4049/jimmunol.0901750] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
RIG-I-like helicases and TLRs are critical sensors in the induction of type I IFN and proinflammatory cytokines to initiate innate immunity against invading pathogens. However, the mechanisms for the full activation of TLR and RIG-I-triggered innate response remain to be fully investigated. Grb2-associated binder 1 (Gab1), a member of scaffolding/adaptor proteins, can mediate signal transduction from many receptors, however, whether and how Gab1 is required for TLR and RIG-I-triggered innate responses remain unknown. In this study, we demonstrated that Gab1 significantly enhances TLR4-, TLR3-, and RIG-I-triggered IL-6, IL-1beta, and IFN-alpha/beta production in macrophages. Gab1 knockdown in primary macrophages or Gab1 deficiency in mouse embryonic fibroblasts significantly suppresses TLR3/4- and RIG-I-triggered production of IL-6, IL-1beta, and IFN-alpha/beta. Consistently, Gab1 deficiency impairs vesicular stomatitis virus (VSV) infection-induced IFN-alpha/beta production. In addition to promoting both MyD88- and TLR/IL-1 receptor domain-containing adaptor protein inducing IFN-beta-dependent MAPKs and NF-kappaB activation, Gab1 enhances PI3K/Akt activation by directly binding p85 in TLR signaling and VSV infection. Accordingly, Gab1 inhibits VSV replication and VSV infection-induced cell damage by inducing type I IFNs and IFN-inducible gene expression via PI3K/Akt pathway. Therefore, Gab1 is needed for full activation of TLR3/4- and RIG-I-triggered innate responses by promoting activation of PI3K/Akt, MAPKs, and NF-kappaB pathways.
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Affiliation(s)
- Yuejuan Zheng
- Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China
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Regulation of virus-triggered type I interferon signaling by cellular and viral proteins. ACTA ACUST UNITED AC 2010; 5:12-31. [PMID: 32215003 PMCID: PMC7088834 DOI: 10.1007/s11515-010-0013-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2009] [Accepted: 12/15/2009] [Indexed: 02/07/2023]
Abstract
Host pattern recognition receptors (PRRs) recognize invading viral pathogens and initiate a series of signaling cascades that lead to the expression of type I interferons (IFNs) and inflammatory cytokines. During the past decade, significant progresses have been made to characterize PRRs such as Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs) and elucidate the molecular mechanisms of TLR- and RLR-mediated signaling. To avoid excessive and harmful immune effects caused by over-activation of these signaling pathways, host cells adopt a number of strategies to regulate them. In addition, invading viruses also employ a variety of mechanisms to inhibit the production of type I IFNs, thereby evading the supervision and clearance by the host. In this review, we briefly summarize the TLR- and RLR-mediated type I IFN signaling and then focus on the mechanisms by which host cellular and viral components regulate the expression of type I IFNs.
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Roles of NF-kappaB in health and disease: mechanisms and therapeutic potential. Clin Sci (Lond) 2009; 116:451-65. [PMID: 19200055 DOI: 10.1042/cs20080502] [Citation(s) in RCA: 147] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The NF-kappaB (nuclear factor kappaB) family of transcription factors are involved in a myriad of activities, including the regulation of immune responses, maturation of immune cells, development of secondary lymphoid organs and osteoclastogenesis. Fine tuning by positive and negative regulators keeps the NF-kappaB signalling pathway in check. Microbial products and genetic alterations in NF-kappaB and other signalling pathway components can lead to deregulation of NF-kappaB signalling in several human diseases, including cancers and chronic inflammatory disorders. NF-kappaB-pathway-specific therapies are being actively investigated, and these hold promises as interventions of NF-kappaB-related ailments.
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Zhang A, Zhang M, Wang Y, Xie H, Zheng S. Calcitriol Prolongs Recipient Survival by Inducing Expression of Zinc-Finger Protein A20 and Inhibiting its Downstream Gene Following Rat Orthotopic Liver Transplantation. Immunopharmacol Immunotoxicol 2008; 28:591-600. [PMID: 17190736 DOI: 10.1080/08923970601067003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Calcitriol has important immunomodulation action and can prolong recipient survival after organ transplantation. The data in this study demonstrated that treatment of liver allograft recipient with calcitriol can protect allograft from acute rejection and prolong recipient's survival. Calcitriol inhibited expression of proinflammatory cytokine such as Interleukin-2 and Interferon-gamma intragraft. It also inhibited expression of nuclear factor kappaB (NF-kappaB) significantly as a result of enhancing its inhibitory protein I kappa B (IkappaB). As well, expression of zinc-finger protein A20 (A20) was enhanced significantly. The results suggest that calcitriol exerts its immunosuppression action in part through inducement of the A20, IkB, inhibition of NF-kB, and resultant proinflammatory expression pathway.
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Affiliation(s)
- Aibin Zhang
- Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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O'Meara SJ, Rodgers K, Godson C. Lipoxins: update and impact of endogenous pro-resolution lipid mediators. Rev Physiol Biochem Pharmacol 2008; 160:47-70. [PMID: 18481030 DOI: 10.1007/112_2006_0606] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Lipoxins (LXs) are endogenously produced eicosanoids that are typically generated by transcellular biosynthesis. These trihydroxytetraene-containing lipid mediators and their stable synthetic analogues possess a wide spectrum of anti-inflammatory and pro-resolution bioactions both in vitro and in vivo. More recently, LXs have emerged as potential anti-fibrotic mediators that may influence pro-fibrotic cytokines and matrix-associated gene expression in response to platelet-derived growth factor (PDGF). Here we review the biosynthesis, metabolism and bioactions of LXs and LX analogues and their therapeutic potential.
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Affiliation(s)
- S J O'Meara
- UCD Conway Institute of Biomolecular and Biomedical Research and UCB Diabetes Research Center, School of Medicine and Medical Sciences, University College Dublin, Belfield, Dublin 4, Ireland
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Abstract
Diverse cellular processes are regulated by tyrosyl phosphorylation, which is controlled by protein-tyrosine kinases (PTKs) and protein-tyrosine phosphatases (PTPs). De-regulated tyrosyl phosphorylation, evoked by gain-of-function mutations and/or over-expression of PTKs, contributes to the pathogenesis of many cancers and other human diseases. PTPs, because they oppose the action of PTKs, had been considered to be prime suspects for potential tumor suppressor genes. Surprisingly, few, if any, tumor suppressor PTPs have been identified. However, the Src homology-2 domain-containing phosphatase Shp2 (encoded by PTPN11) is a bona fide proto-oncogene. Germline mutations in PTPN11 cause Noonan and LEOPARD syndromes, whereas somatic PTPN11 mutations occur in several types of hematologic malignancies, most notably juvenile myelomonocytic leukemia and, more rarely, in solid tumors. Shp2 also is an essential component in several other oncogene signaling pathways. Elucidation of the events underlying Shp2-evoked transformation may provide new insights into oncogenic mechanisms and novel targets for anti-cancer therapy.
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