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Zhang Y, Han Y, Li X, Huang M, Hao P, Kang J. Ultradeep Phosphoproteomics for Assessing Protein Kinase Inhibitor Selectivity on a Proteome Scale. J Med Chem 2025; 68:5845-5855. [PMID: 40009782 DOI: 10.1021/acs.jmedchem.4c03170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/28/2025]
Abstract
The selectivity of protein kinase inhibitors (PKIs) remains a major challenge in drug discovery. In this study, we present an ultradeep phosphoproteomics approach for assessing PKI selectivity and elucidating mechanisms of action using Zanubrutinib as a model. Two complementary phosphoproteomics strategies were employed: phosphopeptides enriched with Zr4+-IMAC in combination with TiO2 beads were analyzed using data-independent acquisition (DIA), while tyrosine phosphopeptides enriched with SH2-Superbinder were analyzed via data-dependent acquisition (DDA). The comprehensive phosphoproteomic analysis identified that 97 and 316 phosphosites were significantly altered upon Zanubrutinib stimulation in the DDA and DIA data sets, respectively. Bioinformatics analysis of these phosphoproteins provided a detailed selectivity profile of Zanubrutinib, offering insights into its mechanism of action at the molecular level. Compared to existing methods, our approach is more comprehensive, has higher throughput, and is more precise─not only for PKI selectivity assessment but also for broader cell signaling research.
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Affiliation(s)
- Yue Zhang
- State Key Laboratory of Chemical Biology, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
- University of Chinese Academy of Sciences, Beijing 101408, China
| | - Ying Han
- School of Life Science and Technology, ShanghaiTech University, Shanghai 200120, China
| | - Xuan Li
- State Key Laboratory of Chemical Biology, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
- School of Physical Science and Technology, ShanghaiTech University, Shanghai 200120, China
| | - Min Huang
- Thermo Fisher Scientific (China), Shanghai 200131, China
| | - Piliang Hao
- School of Life Science and Technology, ShanghaiTech University, Shanghai 200120, China
| | - Jingwu Kang
- State Key Laboratory of Chemical Biology, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
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Wang X, Zhou J, Li X, Liu C, Liu L, Cui H. The Role of Macrophages in Lung Fibrosis and the Signaling Pathway. Cell Biochem Biophys 2024; 82:479-488. [PMID: 38536578 DOI: 10.1007/s12013-024-01253-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 03/13/2024] [Indexed: 08/25/2024]
Abstract
Lung fibrosis is a dysregulated repair process caused by excessive deposition of extracellular matrix that can severely affect respiratory function. Macrophages are a group of immune cells that have multiple functions and can perform a variety of roles. Lung fibrosis develops with the involvement of pro-inflammatory and pro-fibrotic factors secreted by macrophages. The balance between M1 and M2 macrophages has been proposed to play a role in determining the trend and severity of lung fibrosis. New avenues and concepts for preventing and treating lung fibrosis have emerged in recent years through research on mitochondria, Gab proteins, and exosomes. The main topic of this essay is the impact that mitochondria, Gab proteins, and exosomes have on macrophage polarization. In addition, the potential of these factors as targets to enhance lung fibrosis is also explored. We have also collated the functions and mechanisms of signaling pathways associated with the regulation of macrophage polarization such as Notch, TGF-β/Smad, JAK-STAT and cGAS-STING. The goal of this article is to explain the potential benefits of focusing on macrophage polarization as a way to relieve lung fibrosis. We aspire to provide valuable insights that could lead to enhancements in the treatment of this condition.
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Affiliation(s)
- Xingmei Wang
- Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji, 133002, Jilin, China
- Center of Medical Functional Experiment, Yanbian University Medical College, Yanji, 133002, Jilin, China
| | - Jiaxu Zhou
- Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji, 133002, Jilin, China
- Center of Medical Functional Experiment, Yanbian University Medical College, Yanji, 133002, Jilin, China
| | - Xinrui Li
- Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji, 133002, Jilin, China
- Center of Medical Functional Experiment, Yanbian University Medical College, Yanji, 133002, Jilin, China
| | - Chang Liu
- Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji, 133002, Jilin, China
- Center of Medical Functional Experiment, Yanbian University Medical College, Yanji, 133002, Jilin, China
| | - Lan Liu
- Department of Pathology, Affiliated Hospital of Yanbian University, Yanji, 133002, Jilin, China.
| | - Hong Cui
- Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji, 133002, Jilin, China.
- Center of Medical Functional Experiment, Yanbian University Medical College, Yanji, 133002, Jilin, China.
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Zhou J, Tu D, Peng R, Tang Y, Deng Q, Su B, Wang S, Tang H, Jin S, Jiang G, Wang Q, Jin X, Zhang C, Cao J, Bai D. RNF173 suppresses RAF/MEK/ERK signaling to regulate invasion and metastasis via GRB2 ubiquitination in Hepatocellular Carcinoma. Cell Commun Signal 2023; 21:224. [PMID: 37626338 PMCID: PMC10464048 DOI: 10.1186/s12964-023-01241-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 07/22/2023] [Indexed: 08/27/2023] Open
Abstract
BACKGROUND The role of the membrane-associated RING-CH (MARCH) family in carcinogenesis has been widely studied, but the member of this family, RNF173, has not yet been thoroughly explored in the context of hepatocellular carcinoma (HCC). METHODS With the use of an HCC tissue microarray and IHC staining, we aim to determine the differential expression of RNF173 in HCC patients and its clinical significance. The biological role of RNF173 is investigated through in vitro and in vivo experiments. RNA sequencing, mass spectrometry, and immunoprecipitation are performed to uncover the underlying mechanism of RNF173's impact on the development of HCC. RESULTS The mRNA and protein levels of RNF173 were significantly lower in HCC tissues than in normal tissues. HCC patients with low RNF173 expression had shorter overall survival and recurrence-free survival, and RNF173 was significantly correlated with tumor number, tumor capsule, tumor differentiation, and BCLC stage. In addition, in vitro and in vivo experiments showed that RNF173 downregulation exacerbated tumor progression, including migration, invasion, and proliferation. GRB2 is a key molecule in the RAF/MEK/ERK pathway. RNF173 inhibits the RAF/MEK/ERK signaling by ubiquitinating and degrading GRB2, thereby suppressing HCC cell proliferation, invasion and migration. Combining clinical samples, we found that HCC patients with high RNF173 and low GRB2 expression had the best prognosis. CONCLUSION RNF173 inhibits the invasion and metastasis of HCC by ubiquitinating and degrading GRB2, thereby suppressing the RAF/MEK/ERK signaling pathway. RNF173 is an independent risk factor for the survival and recurrence of HCC patients. RNF173 may serve as a novel prognostic molecule and potential therapeutic target for HCC. Video Abstract Graphical abstract Model of RNF173 on RAF/MEK/ERK signaling. RNF173 knockdown resulted in impaired ubiquitination and degradation of GRB2, leading to the activation of the RAF/MEK/ERK signaling pathway and promotion of invasion and metastasis in HCC cells.
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Affiliation(s)
- Jie Zhou
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, 225009, China
| | - Daoyuan Tu
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, 225009, China
| | - Rui Peng
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, 225009, China
| | - Yuhong Tang
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, 225009, China
| | - Qiangwei Deng
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, 225009, China
| | - Bingbing Su
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, 225009, China
| | - Shunyi Wang
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, 225009, China
| | - Hao Tang
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, 225009, China
| | - Shengjie Jin
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, 225009, China
| | - Guoqing Jiang
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, 225009, China
| | - Qian Wang
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, 225009, China
| | - Xin Jin
- Biobank, Clinical Medical College, Yangzhou University, Northern Jiangsu People's Hospital, Yangzhou, China
| | - Chi Zhang
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, 225009, China.
- Subei People's Hospital Hepatobiliary Surgery. Institute of General Surgery, Yangzhou, 225001, China.
| | - Jun Cao
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, 225009, China.
| | - Dousheng Bai
- Department of Hepatobiliary Surgery, Clinical Medical College, Yangzhou University, Yangzhou, 225009, China.
- Subei People's Hospital Hepatobiliary Surgery. Institute of General Surgery, Yangzhou, 225001, China.
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Badachhape AA, Bhandari P, Devkota L, Srivastava M, Tanifum EA, George V, Fox KA, Yallampalli C, Annapragada AV, Ghaghada KB. Nanoparticle Contrast-enhanced MRI for Visualization of Retroplacental Clear Space Disruption in a Mouse Model of Placental Accreta Spectrum (PAS). Acad Radiol 2023; 30:1384-1391. [PMID: 36167627 PMCID: PMC10036264 DOI: 10.1016/j.acra.2022.08.025] [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: 07/14/2022] [Revised: 08/18/2022] [Accepted: 08/22/2022] [Indexed: 11/23/2022]
Abstract
INTRODUCTION Prior preclinical studies established the utility of liposomal nanoparticle blood-pool contrast agents in visualizing the retroplacental clear space (RPCS), a marker of normal placentation, while sparing fetuses from exposure because the agent does not cross the placental barrier. In this work, we characterized RPCS disruption in a mouse model of placenta accreta spectrum (PAS) using these agents. MATERIALS AND METHODS Contrast-enhanced MRI (CE-MRI) and computed tomography (CE-CT) using liposomal nanoparticles bearing gadolinium (liposomal-Gd) and iodine were performed in pregnant Gab3-/- and wild type (WT) mice at day 16 of gestation. CE-MRI was performed on a 1T scanner using a 2D T1-weighted sequence (100×100×600 µm3 voxels) and CE-CT was performed at a higher resolution (70×70×70 µm3 voxels). Animals were euthanized post-imaging and feto-placental units (FPUs) were harvested for histological examination. RPCS conspicuity was scored through blinded assessment of images. RESULTS Pregnant Gab3-/- mice showed elevated rates of complicated pregnancy. Contrast-enhanced imaging demonstrated frank infiltration of the RPCS of Gab3-/- FPUs. RPCS in Gab3-/- FPUs was smaller in volume, demonstrated a heterogeneous signal profile, and received lower conspicuity scores than WT FPUs. Histology confirmed in vivo findings and demonstrated staining consistent with a thinner RPCS in Gab3-/- FPUs. DISCUSSION Imaging of the Gab3-/- mouse model at late gestation with liposomal contrast agents enabled in vivo characterization of morphological differences in the RPCS that could cause the observed pregnancy complications. An MRI-based method for visualizing the RPCS would be valuable for early detection of invasive placentation.
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Affiliation(s)
- Andrew A Badachhape
- Department of Radiology, Baylor College of Medicine, Houston, Texas,; Department of Radiology, Texas Children's Hospital, Houston, Texas 77030
| | - Prajwal Bhandari
- Department of Radiology, Baylor College of Medicine, Houston, Texas,; Department of Radiology, Texas Children's Hospital, Houston, Texas 77030
| | - Laxman Devkota
- Department of Radiology, Baylor College of Medicine, Houston, Texas,; Department of Radiology, Texas Children's Hospital, Houston, Texas 77030
| | - Mayank Srivastava
- Department of Radiology, Texas Children's Hospital, Houston, Texas 77030
| | - Eric A Tanifum
- Department of Radiology, Baylor College of Medicine, Houston, Texas,; Department of Radiology, Texas Children's Hospital, Houston, Texas 77030
| | - Verghese George
- Department of Radiology, Baylor College of Medicine, Houston, Texas
| | - Karin A Fox
- Department of Obstetrics and Gynecology, Texas Children's Hospital, Houston, Texas; Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas
| | - Chandrasekhar Yallampalli
- Department of Obstetrics and Gynecology, Texas Children's Hospital, Houston, Texas; Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas
| | - Ananth V Annapragada
- Department of Radiology, Baylor College of Medicine, Houston, Texas,; Department of Radiology, Texas Children's Hospital, Houston, Texas 77030
| | - Ketan B Ghaghada
- Department of Radiology, Baylor College of Medicine, Houston, Texas,; Department of Radiology, Texas Children's Hospital, Houston, Texas 77030.
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Bryant D, Smith L, Rogers-Broadway KR, Karydis L, Woo J, Blunt MD, Forconi F, Stevenson FK, Goodnow C, Russell A, Humburg P, Packham G, Steele AJ, Strefford JC. Network analysis reveals a major role for 14q32 cluster miRNAs in determining transcriptional differences between IGHV-mutated and unmutated CLL. Leukemia 2023; 37:1454-1463. [PMID: 37169950 PMCID: PMC10317834 DOI: 10.1038/s41375-023-01918-9] [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: 10/28/2022] [Revised: 04/19/2023] [Accepted: 04/21/2023] [Indexed: 05/13/2023]
Abstract
Chronic lymphocytic leukaemia (CLL) cells can express unmutated (U-CLL) or mutated (M-CLL) immunoglobulin heavy chain (IGHV) genes with differing clinical behaviours, variable B cell receptor (BCR) signalling capacity and distinct transcriptional profiles. As it remains unclear how these differences reflect the tumour cells' innate pre/post germinal centre origin or their BCR signalling competence, we applied mRNA/miRNA sequencing to 38 CLL cases categorised into three subsets by IGHV mutational status and BCR signalling capacity. We identified 492 mRNAs and 38 miRNAs differentially expressed between U-CLL and M-CLL, but only 9 mRNAs and 0 miRNAs associated with BCR competence within M-CLL. Of the IGHV-associated miRNAs, (14/38 (37%)) derived from chr14q32 clusters where all miRNAs were co-expressed with the MEG3 lncRNA from a cancer associated imprinted locus. Integrative analysis of miRNA/mRNA data revealed pronounced regulatory potential for the 14q32 miRNAs, potentially accounting for up to 25% of the IGHV-related transcriptome signature. GAB1, a positive regulator of BCR signalling, was potentially regulated by five 14q32 miRNAs and we confirmed that two of these (miR-409-3p and miR-411-3p) significantly repressed activity of the GAB1 3'UTR. Our analysis demonstrates a potential key role of the 14q32 miRNA locus in the regulation of CLL-related gene regulation.
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Affiliation(s)
- Dean Bryant
- School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
| | - Lindsay Smith
- School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
| | | | - Laura Karydis
- School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
| | - Jeongmin Woo
- School of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
| | - Matthew D Blunt
- School of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
| | - Francesco Forconi
- School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
| | - Freda K Stevenson
- School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
| | - Christopher Goodnow
- Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW, 2010, Australia
- Cellular Genomics Futures Institute, UNSW Sydney, Sydney, NSW, Australia
| | - Amanda Russell
- Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW, 2010, Australia
- Cellular Genomics Futures Institute, UNSW Sydney, Sydney, NSW, Australia
| | - Peter Humburg
- Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW, 2010, Australia
- Cellular Genomics Futures Institute, UNSW Sydney, Sydney, NSW, Australia
| | - Graham Packham
- School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
| | - Andrew J Steele
- School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
| | - Jonathan C Strefford
- School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
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Jiang Y, Qu X, Zhang M, Zhang L, Yang T, Ma M, Jing M, Zhang N, Song R, Zhang Y, Yang Z, Zhang Y, Pu Y, Fan J. Identification of a six-gene prognostic signature for bladder cancer associated macrophage. Front Immunol 2022; 13:930352. [PMID: 36275756 PMCID: PMC9582252 DOI: 10.3389/fimmu.2022.930352] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 09/16/2022] [Indexed: 11/13/2022] Open
Abstract
As major components of the tumor microenvironment (TME), tumor-associated macrophages (TAMs) play an exceedingly complicated role in tumor progression and tumorigenesis. However, few studies have reported the specific TAM gene signature in bladder cancer. Herein, this study focused on developing a TAM-related prognostic model in bladder cancer patients based on The Cancer Genome Atlas (TCGA) data. Weighted Gene Co-Expression Network Analysis (WGCNA) was used to identify key genes related to TAM (M2 macrophage). Gene ontology (GO) enrichment and the Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway analysis showed the functional categories of the key genes. Simultaneously, we used the Least Absolute Shrinkage and Selection Operator (LASSO) and univariate and multivariate Cox regressions to establish a TMA-related prognostic model containing six key genes: TBXAS1, GYPC, HPGDS, GAB3, ADORA3, and FOLR2. Subsequently, single-cell sequencing data downloaded from Gene Expression Omnibus (GEO) suggested that the six genes in the prognostic model were expressed in TAM specifically and may be involved in TAM polarization. In summary, our research uncovered six-TAM related genes that may have an effect on risk stratification in bladder cancer patients and could be regarded as potential TAM-related biomarkers.
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Affiliation(s)
- Yunzhong Jiang
- Department of Urology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Xiaowei Qu
- Department of Geriatrics, The Yan’an University Xianyang Hospital, Xianyang, China
| | - Mengzhao Zhang
- Department of Urology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Lu Zhang
- Department of Urology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Tao Yang
- Department of Urology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Minghai Ma
- Department of Urology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Minxuan Jing
- Department of Urology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Nan Zhang
- Department of Urology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Rundong Song
- Department of Urology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Yuanquan Zhang
- Department of Urology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Zezhong Yang
- Department of Urology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Yaodong Zhang
- Department of Urology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Yuanchun Pu
- Department of Urology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Jinhai Fan
- Department of Urology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Oncology Research Lab, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi’an, China
- *Correspondence: Jinhai Fan,
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Niu C, Li M, Chen Y, Zhang X, Zhu S, Zhou X, Zhou L, Li Z, Xu J, Hu JF, Wang Y, Cui J. LncRNA NCAL1 potentiates natural killer cell cytotoxicity through the Gab2-PI3K-AKT pathway. Front Immunol 2022; 13:970195. [PMID: 36248894 PMCID: PMC9554105 DOI: 10.3389/fimmu.2022.970195] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 08/31/2022] [Indexed: 11/24/2022] Open
Abstract
Natural killer (NK) cells perform immune surveillance functions in tumors. The antitumor effects of NK cells are closely related to tumor occurrence and development. However, the molecular factors that determine NK cell antitumor activity remain to be characterized. In the present study, we identified a novel long noncoding RNA (lncRNA), NK cell activity-associated lncRNA 1 (NCAL1), and investigated its function in NK cells. NCAL1 was primarily located in NK cell nuclei, where it functioned by activating Gab2, a scaffold protein with an essential role in immune cells. Gab2 positively regulated the killing activity of NK cells. Mechanistically, NCAL1 upregulated Gab2 epigenetically by binding to the Gab2 promoter, which decreased methylation, recruited the transcription factor Sp1, and increased H3K4me3 and H3K27ac levels in the Gab2 promoter. Furthermore, NCAL1 enhanced the cytotoxicity of NK cells toward tumor cells through the Gab2-PI3K-AKT pathway. Thus, NCAL1 potentiates NK cell cytotoxicity and is a promising therapeutic target to improve NK cell therapy.
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Affiliation(s)
- Chao Niu
- Department of Cancer Center, First Hospital, Jilin University, Changchun, China
| | - Min Li
- Department of Cancer Center, First Hospital, Jilin University, Changchun, China
| | - Yongchong Chen
- Department of Cancer Center, First Hospital, Jilin University, Changchun, China
| | - Xiaoying Zhang
- Department of Cancer Center, First Hospital, Jilin University, Changchun, China
| | - Shan Zhu
- Department of Translational Medicine, First Hospital, Jilin University, Changchun, China
| | - Xin Zhou
- Cancer Institute, First Hospital, Jilin University, Changchun, China
| | - Lei Zhou
- Department of Cancer Center, First Hospital, Jilin University, Changchun, China
| | - Zhaozhi Li
- Department of Cancer Center, First Hospital, Jilin University, Changchun, China
| | - Jianting Xu
- Department of Cancer Center, First Hospital, Jilin University, Changchun, China
| | - Ji-fan Hu
- Department of Cancer Center, First Hospital, Jilin University, Changchun, China
- Stanford University Medical School, Veterans Affairs (VA) Palo Alto Health Care System, Palo Alto, CA, United States
- *Correspondence: Jiuwei Cui, ; Yufeng Wang, ; Ji-fan Hu, ;
| | - Yufeng Wang
- Cancer Institute, First Hospital, Jilin University, Changchun, China
- *Correspondence: Jiuwei Cui, ; Yufeng Wang, ; Ji-fan Hu, ;
| | - Jiuwei Cui
- Department of Cancer Center, First Hospital, Jilin University, Changchun, China
- *Correspondence: Jiuwei Cui, ; Yufeng Wang, ; Ji-fan Hu, ;
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Liu R, Sun Y, Chen S, Hong Y, Lu Z. FOXD3 and GAB2 as a pair of rivals antagonistically control hepatocellular carcinogenesis. FEBS J 2022; 289:4536-4548. [DOI: 10.1111/febs.16403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 09/05/2021] [Accepted: 02/15/2022] [Indexed: 02/07/2023]
Affiliation(s)
- Ruimin Liu
- School of Pharmaceutical Sciences State Key Laboratory of Cellular Stress Biology Xiamen University Xiamen China
| | - Yan Sun
- School of Pharmaceutical Sciences State Key Laboratory of Cellular Stress Biology Xiamen University Xiamen China
| | - Shuai Chen
- School of Pharmaceutical Sciences State Key Laboratory of Cellular Stress Biology Xiamen University Xiamen China
| | - Yun Hong
- School of Pharmaceutical Sciences State Key Laboratory of Cellular Stress Biology Xiamen University Xiamen China
| | - Zhongxian Lu
- School of Pharmaceutical Sciences State Key Laboratory of Cellular Stress Biology Xiamen University Xiamen China
- Fujian Provincial Key Laboratory of Innovative Drug Target Research School of Pharmaceutical Sciences Xiamen China
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9
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Scaffolding protein Gab2 is involved in postnatal development and lipopolysaccharide-induced activation of microglia in the mouse brain. Biochem Biophys Res Commun 2021; 567:112-117. [PMID: 34146905 DOI: 10.1016/j.bbrc.2021.06.028] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Accepted: 06/07/2021] [Indexed: 12/30/2022]
Abstract
Grb2-associated-binding protein-2 (Gab2) is a member of the Gab/DOS family and functions as an adapter protein downstream of several growth factor signaling pathways. Gab2 is considered an Alzheimer's disease susceptibility gene. However, the role of Gab2 in the brain is still largely unknown. Herein, we report that Gab2 is involved in the postnatal development of microglia in mice. The Gab2 expression in the brain was detected at postnatal day 1 (P1) and increased until P14 but decreased thereafter. The tyrosine phosphorylation of Gab2 (pGab2) was also detected at P1 and increased until P14. Next, we focused on microglial development in Gab2 knockout and heterozygous mice. Although differences were not detected in the cytoplasmic area of Iba1-labeled microglia between Gab2(±) and Gab2(-/-) mice, the analysis of CD68 and cathepsin D (indicators of microglial lysosomal activation) immunolabeling within Iba1+ cells revealed significant underdevelopment of microglial lysosomes in Gab2(-/-) mice at P60. In addition to the developmental abnormality of microglia in Gab2(-/-) mice, lipopolysaccharide-induced lysosomal activation was selectively suppressed in Gab2(-/-) mice compared to that in Gab2(±) mice. Our findings suggest that Gab2 is involved not only in postnatal development but also in lysosomal activation of microglia, therefore Gab2 dysfunction in microglia might potentially contribute to the development of neurodegenerative diseases.
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10
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Qiao XR, Zhang X, Mu L, Tian J, Du Y. GRB2-associated binding protein 2 regulates multiple pathways associated with the development of prostate cancer. Oncol Lett 2020; 20:99. [PMID: 32831918 PMCID: PMC7439102 DOI: 10.3892/ol.2020.11960] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Accepted: 05/18/2020] [Indexed: 12/24/2022] Open
Abstract
The development of prostate cancer is complicated and involves a number of tumor-associated gene expression level abnormalities. Gene chip technology is a high-throughput method that can detect gene expression levels in different tissues and cells on a large scale. In the present study, gene chip technology was used to screen differentially expressed genes in PC-3 human prostate cancer cells following GRB-associated binding protein 2 (GAB2) gene knockdown, and the corresponding biological information was analyzed to investigate the role of GAB2 in prostate cancer. The PC-3 human prostate cancer cell GAB2 gene was knocked out and gene chip hybridization and bioinformatics methods were used to analyze the classical pathway and predict upstream regulatory molecules, disease and function associations and genetic interaction networks. According to the screening conditions |fold change|>1 and P<0.05, 1,242 differential genes were screened; 665 genes were upregulated, and 577 genes were downregulated. Ingenuity Pathway Analysis software demonstrated that GAB2 regulates pathways, such as the superpathway of cholesterol biosynthesis and p53 signaling in cells, and serves a role in diseases and functions such as 'non-melanoma solid tumors', 'viral infections' and 'morbidity or mortality'. In the occurrence and development of prostate cancer, factors such as the activation of genes involved in the proliferative cycle, abnormalities in metabolism-associated enzyme gene activities and viral infection play key roles. The present study provides novel research directions and therapeutic targets for prostate cancer.
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Affiliation(s)
- Xiang-Rui Qiao
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.,Key Laboratory of Molecular Cardiology, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi 710061, P.R. China
| | - Xinwei Zhang
- Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi 710061, P.R. China.,Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Lijun Mu
- Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi 710061, P.R. China
| | - Juanhua Tian
- Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi 710061, P.R. China
| | - Yuefeng Du
- Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi 710061, P.R. China.,Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
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11
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Oliver KF, Wahl AM, Dick M, Toenges JA, Kiser JN, Galliou JM, Moraes JGN, Burns GW, Dalton J, Spencer TE, Neibergs HL. Genomic Analysis of Spontaneous Abortion in Holstein Heifers and Primiparous Cows. Genes (Basel) 2019; 10:genes10120954. [PMID: 31766405 PMCID: PMC6969913 DOI: 10.3390/genes10120954] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 11/15/2019] [Accepted: 11/19/2019] [Indexed: 12/18/2022] Open
Abstract
Background: The objectives of this study were to identify loci, positional candidate genes, gene-sets, and pathways associated with spontaneous abortion (SA) in cattle and compare these results with previous human SA studies to determine if cattle are a good SA model for humans. Pregnancy was determined at gestation day 35 for Holstein heifers and cows. Genotypes from 43,984 SNPs of 499 pregnant heifers and 498 pregnant cows that calved at full term (FT) were compared to 62 heifers and 28 cows experiencing SA. A genome-wide association analysis, gene-set enrichment analysis–single nucleotide polymorphism, and ingenuity pathway analysis were used to identify regions, pathways, and master regulators associated with SA in heifers, cows, and a combined population. Results: Twenty-three loci and 21 positional candidate genes were associated (p < 1 × 10−5) with SA and one of these (KIR3DS1) has been associated with SA in humans. Eight gene-sets (NES > 3.0) were enriched in SA and one was previously reported as enriched in human SA. Four master regulators (p < 0.01) were associated with SA within two populations. Conclusions: One locus associated with SA was validated and 39 positional candidate and leading-edge genes and 2 gene-sets were enriched in SA in cattle and in humans.
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Affiliation(s)
- Kayleen F. Oliver
- Department of Animal Sciences and Center for Reproductive Biology, Washington State University, Pullman, WA 646310, USA; (K.F.O.); (A.M.W.); (M.D.); (J.A.T.); (J.N.K.); (J.M.G.)
| | - Alexandria M. Wahl
- Department of Animal Sciences and Center for Reproductive Biology, Washington State University, Pullman, WA 646310, USA; (K.F.O.); (A.M.W.); (M.D.); (J.A.T.); (J.N.K.); (J.M.G.)
| | - Mataya Dick
- Department of Animal Sciences and Center for Reproductive Biology, Washington State University, Pullman, WA 646310, USA; (K.F.O.); (A.M.W.); (M.D.); (J.A.T.); (J.N.K.); (J.M.G.)
| | - Jewel A. Toenges
- Department of Animal Sciences and Center for Reproductive Biology, Washington State University, Pullman, WA 646310, USA; (K.F.O.); (A.M.W.); (M.D.); (J.A.T.); (J.N.K.); (J.M.G.)
| | - Jennifer N. Kiser
- Department of Animal Sciences and Center for Reproductive Biology, Washington State University, Pullman, WA 646310, USA; (K.F.O.); (A.M.W.); (M.D.); (J.A.T.); (J.N.K.); (J.M.G.)
| | - Justine M. Galliou
- Department of Animal Sciences and Center for Reproductive Biology, Washington State University, Pullman, WA 646310, USA; (K.F.O.); (A.M.W.); (M.D.); (J.A.T.); (J.N.K.); (J.M.G.)
| | - Joao G. N. Moraes
- Animal Sciences Research Center, Division of Animal Sciences, University of Missouri, Columbia, MO S158A, USA (G.W.B.); (T.E.S.)
| | - Gregory W. Burns
- Animal Sciences Research Center, Division of Animal Sciences, University of Missouri, Columbia, MO S158A, USA (G.W.B.); (T.E.S.)
| | - Joseph Dalton
- Department of Animal and Veterinary Sciences, University of Idaho, Caldwell, ID 1904 E, USA;
| | - Thomas E. Spencer
- Animal Sciences Research Center, Division of Animal Sciences, University of Missouri, Columbia, MO S158A, USA (G.W.B.); (T.E.S.)
| | - Holly L. Neibergs
- Department of Animal Sciences and Center for Reproductive Biology, Washington State University, Pullman, WA 646310, USA; (K.F.O.); (A.M.W.); (M.D.); (J.A.T.); (J.N.K.); (J.M.G.)
- Correspondence: ; Tel.: +1-1509-335-6491
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12
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Chen XX, Guo RR, Cao XP, Tan L, Tan L, Alzheimer’s Disease Neuroimaging Initiative. The impact of GAB2 genetic variations on cerebrospinal fluid markers in Alzheimer's disease. ANNALS OF TRANSLATIONAL MEDICINE 2018; 6:171. [PMID: 29951493 PMCID: PMC5994512 DOI: 10.21037/atm.2018.04.11] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Accepted: 04/03/2018] [Indexed: 11/06/2022]
Abstract
BACKGROUND Growth factor receptor-bound protein-associated binding protein 2 gene (GAB2) has been regarded as one of the susceptibility gene associated with Alzheimer's disease (AD). However, the role of GAB2 polymorphisms on cerebrospinal fluid (CSF) proteins in AD continuum remains unclear. METHODS We evaluated the connection between four single nucleotide polymorphisms (SNPs) of GAB2 and AD-related CSF biomarkers including amyloid β (Aβ), total tau (T-tau) and phosphorylated tau (P-tau) level in 627 Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects. RESULTS rs1385600 and rs1007837 were significantly associated with all the three biomarkers in CSF (rs1385600: Aβ Pc =0.0112, T-tau Pc =0.0356, P-tau Pc =0.0116; rs1007837: Aβ Pc =0.0058, T-tau Pc =0.0278, P-tau Pc =0.0231). rs2373115 only showed significant association with Aβ and P-tau (Aβ, Pc=0.0398, P-tau, Pc=0.0329). rs10793294 showed no significant association with all the three biomarkers. CONCLUSIONS Our study suggested that GAB2 variants were significantly associated with the level of the three CSF biomarkers, which further supported that GAB2 genetic variation modulates AD risk via the alteration of both Aβ and tau pathology.
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Affiliation(s)
- Xiao-Xiao Chen
- Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, China
| | - Run-Rong Guo
- Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, China
| | - Xi-Peng Cao
- Clinical Research Center, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, China
| | - Lin Tan
- Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, China
| | - Lan Tan
- Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, China
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13
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Cheng M, Niu Y, Fan J, Chi X, Liu X, Yang W. Interferon down-regulation of miR-1225-3p as an antiviral mechanism through modulating Grb2-associated binding protein 3 expression. J Biol Chem 2018; 293:5975-5986. [PMID: 29496996 PMCID: PMC5912462 DOI: 10.1074/jbc.ra117.000738] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Revised: 02/09/2018] [Indexed: 12/14/2022] Open
Abstract
Induction of interferons (IFNs) is a central event of antiviral innate immunity. As crucial posttranscriptional regulators, microRNAs (miRNAs) are important for IFN-mediated host defense. Although screening has indicated a substantial number of miRNAs to be differentially expressed after IFN stimulation, the detailed mechanisms of these miRNAs in the antiviral response are underexplored and of great significance. Here, we show that hsa-miR-1225-3p is specifically down-regulated by type I IFN through the IFN/JAK/STAT signaling pathway. Silencing endogenous miR-1225-3p inhibited infection by multiple IFN-susceptible viruses, including hepatitis C virus, Sendai virus, and Newcastle disease virus. In contrast, overexpression of miR-1225-3p impaired the antiviral effect of IFNs and facilitated viral infection. Regarding the mechanism, we identified growth factor receptor-bound protein 2-associated binding protein 3 (GAB3) as a direct target of miR-1225-3p. GAB3 expression was up-regulated by IFN, and overexpression of GAB3 demonstrated potent antiviral effects through enhancing IFN response and virus-triggered innate immune activation. Taken together, our findings reveal the biological function of miR-1225-3p for the first time and propose a novel antiviral regulation pathway in which miRNA and GAB3 participate. This study contributes to the understanding of host miRNA participation in antiviral processes of IFN.
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Affiliation(s)
- Min Cheng
- From the MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100176, China
| | - Yuqiang Niu
- From the MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100176, China
| | - Jingjing Fan
- From the MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100176, China
| | - Xiaojing Chi
- From the MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100176, China
| | - Xiuying Liu
- From the MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100176, China
| | - Wei Yang
- From the MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100176, China
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14
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Gu DH, Mao JH, Pan XD, Zhu H, Chen X, Zheng B, Shan Y. microRNA-302c-3p inhibits renal cell carcinoma cell proliferation by targeting Grb2-associated binding 2 (Gab2). Oncotarget 2018; 8:26334-26343. [PMID: 28412750 PMCID: PMC5432261 DOI: 10.18632/oncotarget.15463] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2017] [Accepted: 02/02/2017] [Indexed: 11/25/2022] Open
Abstract
The expression and biological function of Grb2-associated binding 2 (Gab2) in renal cell carcinoma (RCC) cells was tested here. We showed that Gab2 expression was significantly elevated in human RCC tissues and RCC cells. It was correlated with over-activation of Akt and downregulation of microRNA-302c-3p ("miR-302c-3p"), a putative Gab2-targeting microRNA. Knockdown of Gab2 inhibited Akt activation and 786-O RCC cell proliferation. Reversely, forced over-expression of Gab2 led to Akt hyper-activation to facilitate 786-O cell proliferation. Exogenous expression of miR-302c caused Gab2 downregulation, Akt inhibition and 786-O cell proliferation inhibition. On the other hand, miR-302c-3p depletion by expressing its anti-sense ("antagomiR-302c") led to Gab2 upregulation, Akt activation and increased 786-O cell proliferation. Significantly, miR-302c-3p failed to affect the proliferation of 786-O cells with shRNA-depleted Gab2. Together, we suggest that miR-302c-3p depletion in human RCC cells leads to Gab2 over-expression, Akt hyper-activation and cell proliferation.
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Affiliation(s)
- Dong-Hua Gu
- The Department of Urology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Jia-Hui Mao
- Department of Pathophysiology, Nantong University School of Medicine, Nantong, China
| | - Xiao-Dong Pan
- The Department of Urology, The Second Affiliated Hospital of Soochow University, Suzhou, China.,The Department of Urology, The Second Affiliated Hospital of Nantong University, Nantong, China
| | - Hua Zhu
- The Department of Urology, The Second Affiliated Hospital of Nantong University, Nantong, China
| | - Xinfeng Chen
- The Department of Urology, The Second Affiliated Hospital of Nantong University, Nantong, China
| | - Bing Zheng
- The Department of Urology, The Second Affiliated Hospital of Nantong University, Nantong, China
| | - Yuxi Shan
- The Department of Urology, The Second Affiliated Hospital of Soochow University, Suzhou, China
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15
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Guo X, Li T, Xu Y, Xu X, Zhu Z, Zhang Y, Xu J, Xu K, Cheng H, Zhang X, Ke Y. Increased levels of Gab1 and Gab2 adaptor proteins skew interleukin-4 (IL-4) signaling toward M2 macrophage-driven pulmonary fibrosis in mice. J Biol Chem 2017; 292:14003-14015. [PMID: 28687632 DOI: 10.1074/jbc.m117.802066] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Revised: 07/06/2017] [Indexed: 12/24/2022] Open
Abstract
M2-polarized macrophages, also known as alternatively activated macrophages, have long been associated with pulmonary fibrosis; however, the mechanism has not been fully defined. Gab1 and Gab2 proteins belong to the Gab family of adaptors and are integral components of the signal specificity in response to various extracellular stimuli. In this report, we found that levels of both Gab1 and Gab2 were elevated in M2-polarized macrophages isolated from bleomycin-induced fibrotic lungs. In vitro Gab1/2 deficiency in bone marrow-derived macrophages abrogated IL-4-mediated M2 polarization. Furthermore, in vivo conditional removal of Gab1 (Gab1MyKO) and germ line knock-out of Gab2 (Gab2-/-) in macrophages prevented a bias toward the M2 phenotype and attenuated bleomycin-induced fibrotic lung remodeling. In support of these observations, Gab1/2 were involved in responses predominated by IL-4 signaling, an essential determinant for macrophage M2 polarization. Further investigation revealed that both Gab1 and -2 are recruited to the IL-4 receptor, synergistically enhancing downstream signal amplification but conferring IL-4 signal preference. Mechanistically, the loss of Gab1 attenuated AKT activation, whereas the absence of Gab2 suppressed STAT6 activation in response to IL-4 stimulation, both of which are commonly attributed to M2-driven pulmonary fibrosis in mice. Taken together, these observations define a non-redundant role of Gab docking proteins in M2 polarization, adding critical insights into the pathogenesis of idiopathic pulmonary fibrosis.
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Affiliation(s)
- Xiaohong Guo
- From the Department of Pathology and Pathophysiology and Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
| | - Tingting Li
- From the Department of Pathology and Pathophysiology and Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
| | - Yun Xu
- From the Department of Pathology and Pathophysiology and Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
| | - Xiayan Xu
- From the Department of Pathology and Pathophysiology and Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
| | - Zhengyi Zhu
- From the Department of Pathology and Pathophysiology and Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
| | - Yun Zhang
- From the Department of Pathology and Pathophysiology and Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
| | - Jiaqi Xu
- From the Department of Pathology and Pathophysiology and Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
| | - Kaihong Xu
- Department of Gynecology, Women's Hospital School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, China
| | - Hongqiang Cheng
- From the Department of Pathology and Pathophysiology and Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang 310003, China
| | - Xue Zhang
- From the Department of Pathology and Pathophysiology and Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang 310003, China.
| | - Yuehai Ke
- From the Department of Pathology and Pathophysiology and Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang 310003, China.
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16
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Hu L, Liu R. Expression of Gab1 Is Associated with Poor Prognosis of Patients with Epithelial Ovarian Cancer. TOHOKU J EXP MED 2017; 239:177-84. [PMID: 27302321 DOI: 10.1620/tjem.239.177] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Growth factor receptor-bound protein-2 (Grb2) can act as the scaffold protein recruiting other molecules to the stimulated receptors. Grb2-associated binding protein 1 (Gab1) is involved in cell proliferation, and its expression may enhance the carcinogenesis and cancer progression. However, the function of Gab1 remains to be investigated. Epithelial ovarian cancer (EOC) is the most lethal malignancy in the female reproductive system with increasing incidence and unsatisfied overall survival (OS). We investigated the expression of Gab1 in EOC tissues and the correlations between Gab1 expression and the clinicopathological characteristics of patients with EOC using Spearman rank test. The staining results were evaluated based on both the percentage of Gab1-positive tumor cells and the staining intensity for Gab1 expression. Kaplan-Meier survival analysis and Cox proportional hazards analysis were used to compare the postoperative OS between EOC patients with high Gab1 expression and those with low Gab1 expression. The high expression of Gab1 was positively correlated with advanced FIGO stage and lymph node metastasis of EOC. Univariate analysis showed that advanced FIGO stage, pathological grade, lymph node metastasis or Gab1 expression were associated with poor OS. Moreover, multivariate analysis revealed that Gab1 expression could be an independent prognostic factor for the poor OS of EOC patients (P = 0.042). We propose that Gab1 expression is correlated with poor prognosis of EOC patients and may act as an independent prognostic indicator.
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Affiliation(s)
- Lingling Hu
- Department of Gynecology, Linyi People's Hospital
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17
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Do DC, Agrawal A, Luo X, Gao P. Gab1, a therapeutic target for allergic asthma? ACTA ACUST UNITED AC 2017; 2. [PMID: 30148256 DOI: 10.21037/jxym.2017.03.02] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Danh C Do
- Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, USA
| | - Arshi Agrawal
- Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, USA.,Maulana Azad Medical College, New Delhi, India
| | - Xiaoyan Luo
- Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, USA
| | - Peisong Gao
- Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, USA
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18
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Jia P, Li F, Gu W, Zhang W, Cai Y. Gab3 overexpression in human glioma mediates Akt activation and tumor cell proliferation. PLoS One 2017; 12:e0173473. [PMID: 28291820 PMCID: PMC5349442 DOI: 10.1371/journal.pone.0173473] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Accepted: 02/22/2017] [Indexed: 11/18/2022] Open
Abstract
This current study tested expression and potential biological functions of Gab3 in human glioma. Gab3 mRNA and protein expression was significantly elevated in human glioma tissues and glioma cells. Its level was however low in normal brain tissues and primary human astrocytes. In both established (U251MG cell line) and primary human glioma cells, Gab3 knockdown by shRNA/siRNA significantly inhibited Akt activation and cell proliferation. Reversely, forced Gab3 overexpression in U251MG cells promoted Akt activation and cell proliferation. In vivo, the growth of U251MG tumors in nude mice was inhibited following expressing Gab3 shRNA. Akt activation in cancer tissues was also suppressed by Gab3 shRNA. Together, we conclude that Gab3 overexpression in human glioma mediates Akt activation and cancer cell proliferation.
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Affiliation(s)
- Pifeng Jia
- Department of Neurosurgery, RuiJin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Feng Li
- Department of Neurosurgery, RuiJin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weiting Gu
- Department of Neurosurgery, RuiJin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weifeng Zhang
- Department of Neurosurgery, RuiJin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yu Cai
- Department of Neurosurgery, RuiJin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- * E-mail:
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Pha K, Navarro L. Yersinia type III effectors perturb host innate immune responses. World J Biol Chem 2016; 7:1-13. [PMID: 26981193 PMCID: PMC4768113 DOI: 10.4331/wjbc.v7.i1.1] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Revised: 09/02/2015] [Accepted: 11/04/2015] [Indexed: 02/05/2023] Open
Abstract
The innate immune system is the first line of defense against invading pathogens. Innate immune cells recognize molecular patterns from the pathogen and mount a response to resolve the infection. The production of proinflammatory cytokines and reactive oxygen species, phagocytosis, and induced programmed cell death are processes initiated by innate immune cells in order to combat invading pathogens. However, pathogens have evolved various virulence mechanisms to subvert these responses. One strategy utilized by Gram-negative bacterial pathogens is the deployment of a complex machine termed the type III secretion system (T3SS). The T3SS is composed of a syringe-like needle structure and the effector proteins that are injected directly into a target host cell to disrupt a cellular response. The three human pathogenic Yersinia spp. (Y. pestis, Y. enterocolitica, and Y. pseudotuberculosis) are Gram-negative bacteria that share in common a 70 kb virulence plasmid which encodes the T3SS. Translocation of the Yersinia effector proteins (YopE, YopH, YopT, YopM, YpkA/YopO, and YopP/J) into the target host cell results in disruption of the actin cytoskeleton to inhibit phagocytosis, downregulation of proinflammatory cytokine/chemokine production, and induction of cellular apoptosis of the target cell. Over the past 25 years, studies on the Yersinia effector proteins have unveiled tremendous knowledge of how the effectors enhance Yersinia virulence. Recently, the long awaited crystal structure of YpkA has been solved providing further insights into the activation of the YpkA kinase domain. Multisite autophosphorylation by YpkA to activate its kinase domain was also shown and postulated to serve as a mechanism to bypass regulation by host phosphatases. In addition, novel Yersinia effector protein targets, such as caspase-1, and signaling pathways including activation of the inflammasome were identified. In this review, we summarize the recent discoveries made on Yersinia effector proteins and their contribution to Yersinia pathogenesis.
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20
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Bromo-honaucin A inhibits osteoclastogenic differentiation in RAW 264.7 cells via Akt and ERK signaling pathways. Eur J Pharmacol 2015; 769:100-9. [PMID: 26550952 DOI: 10.1016/j.ejphar.2015.11.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Revised: 10/20/2015] [Accepted: 11/02/2015] [Indexed: 11/20/2022]
Abstract
Osteoclasts are unique bone remodeling cells derived from multinucleated myeloid progenitor cells. They play homeostatic vital roles in skeletal modeling and remodeling but also destroy bone masses in many pathological conditions such as osteoporosis and rheumatoid arthritis. Receptor activation of NF-κB ligand (RANKL) is essential to osteoclastogenesis. In this study, we investigated the effects of bromo-honaucin A (Br-H A) isolated from Leptolyngbya crossbyana (cyanobacterium). To investigate the mechanism of the inhibitory effect of Br-H A on osteoclastogenesis, we employed Br-H Ain RANKL-treated murine monocyte/macrophage RAW 264.7 cells for osteoclastic differentiation in-vitro. The inhibitory effects on in-vitro osteoclastogenesis was evaluated by counting the number of Tartarate resistant acid phospatase (TRAP) positive multinucleated cells and by measuring the expression level of osteoclast-specific genes like matrix metalloproteinase 9 (MMP9), cathepsin K (CATH K), GRB2-associated-binding protein 2 (GAB2), c-terminal myc kinase (C-MYC), C-terminal Src kinase (C-SRC) and Microphthalmia-associated transcription factor (MITF). Moreover, Br-H A blocked the resorbing capacity of RAW 264.7 cells on calcium phosphate-coated plates. Finally, Br-H A clearly decreased the expression of Akt and also decreased the activation of ERK. Thus, the study identifies Br-H A as potent inhibitor potentialin the treatment of diseases involving abnormal bone lysis such as osteoporosis, rheumatoid arthritis, and periodontal bone degradation.
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21
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Ding CB, Yu WN, Feng JH, Luo JM. Structure and function of Gab2 and its role in cancer (Review). Mol Med Rep 2015; 12:4007-4014. [PMID: 26095858 PMCID: PMC4526075 DOI: 10.3892/mmr.2015.3951] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2014] [Accepted: 05/19/2015] [Indexed: 12/30/2022] Open
Abstract
The docking proteins of the Grb-associated binder (Gab) family transduce cellular signals between receptors and intracellular downstream effectors, and provide a platform for protein-protein interactions. Gab2, a key member of the Gab family of proteins, is involved in the amplification and integration of signal transduction, evoked by a variety of extracellular stimuli, including growth factors, cytokines and antigen receptors. Gab2 protein lacks intrinsic catalytic activity; however, when phosphorylated by protein-tyrosine kinases (PTKs), Gab2 recruits several Src homology-2 (SH2) domain-containing proteins, including the SH2-containing protein tyrosine phosphatase 2 (SHP2), the p85 subunit of phosphoinositide-3 kinase (PI3K), phospholipase C-γ (PLCγ)1, Crk, and GC-GAP. Through these interactions, the Gab2 protein triggers various downstream signal effectors, including SHP2/rat sarcoma viral oncogene/RAF/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase and PI3K/AKT, involved in cell growth, differentiation, migration and apoptosis. It has been previously reported that aberrant Gab2 and/or Gab2 signaling is closely associated with human tumorigenesis, particularly in breast cancer, leukemia and melanoma. The present review aimed to focus on the structure and effector function of Gab2, its role in cancer and its potential for use as an effective therapeutic target.
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Affiliation(s)
- Chen-Bo Ding
- Department of Immunology and Immunology Innovation Base for Postgraduate Education in Guizhou Province, Zunyi Medical University, Zunyi, Guizhou 563099, P.R. China
| | - Wei-Na Yu
- Department of Immunology and Immunology Innovation Base for Postgraduate Education in Guizhou Province, Zunyi Medical University, Zunyi, Guizhou 563099, P.R. China
| | - Ji-Hong Feng
- Department of Oncology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563099, P.R. China
| | - Jun-Min Luo
- Department of Immunology and Immunology Innovation Base for Postgraduate Education in Guizhou Province, Zunyi Medical University, Zunyi, Guizhou 563099, P.R. China
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Sharma A, Menche J, Huang CC, Ort T, Zhou X, Kitsak M, Sahni N, Thibault D, Voung L, Guo F, Ghiassian SD, Gulbahce N, Baribaud F, Tocker J, Dobrin R, Barnathan E, Liu H, Panettieri RA, Tantisira KG, Qiu W, Raby BA, Silverman EK, Vidal M, Weiss ST, Barabási AL. A disease module in the interactome explains disease heterogeneity, drug response and captures novel pathways and genes in asthma. Hum Mol Genet 2015; 24:3005-20. [PMID: 25586491 DOI: 10.1093/hmg/ddv001] [Citation(s) in RCA: 131] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2014] [Accepted: 01/05/2015] [Indexed: 01/24/2023] Open
Abstract
Recent advances in genetics have spurred rapid progress towards the systematic identification of genes involved in complex diseases. Still, the detailed understanding of the molecular and physiological mechanisms through which these genes affect disease phenotypes remains a major challenge. Here, we identify the asthma disease module, i.e. the local neighborhood of the interactome whose perturbation is associated with asthma, and validate it for functional and pathophysiological relevance, using both computational and experimental approaches. We find that the asthma disease module is enriched with modest GWAS P-values against the background of random variation, and with differentially expressed genes from normal and asthmatic fibroblast cells treated with an asthma-specific drug. The asthma module also contains immune response mechanisms that are shared with other immune-related disease modules. Further, using diverse omics (genomics, gene-expression, drug response) data, we identify the GAB1 signaling pathway as an important novel modulator in asthma. The wiring diagram of the uncovered asthma module suggests a relatively close link between GAB1 and glucocorticoids (GCs), which we experimentally validate, observing an increase in the level of GAB1 after GC treatment in BEAS-2B bronchial epithelial cells. The siRNA knockdown of GAB1 in the BEAS-2B cell line resulted in a decrease in the NFkB level, suggesting a novel regulatory path of the pro-inflammatory factor NFkB by GAB1 in asthma.
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Affiliation(s)
- Amitabh Sharma
- Center for Complex Networks Research, Department of Physics, Northeastern University, Boston, MA 02115, USA Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Jörg Menche
- Center for Complex Networks Research, Department of Physics, Northeastern University, Boston, MA 02115, USA Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA Department of Theoretical Physics, Budapest University of Technology and Economics, H1111, Budapest, Hungary Center for Network Science, Central European University, Nador u. 9, 1051 Budapest, Hungary
| | - C Chris Huang
- Janssen Research & Development, Inc., 1400 McKean Road, Spring House, PA 19477, USA
| | - Tatiana Ort
- Janssen Research & Development, Inc., 1400 McKean Road, Spring House, PA 19477, USA
| | - Xiaobo Zhou
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Maksim Kitsak
- Center for Complex Networks Research, Department of Physics, Northeastern University, Boston, MA 02115, USA Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Nidhi Sahni
- Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Derek Thibault
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Linh Voung
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Feng Guo
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Susan Dina Ghiassian
- Center for Complex Networks Research, Department of Physics, Northeastern University, Boston, MA 02115, USA Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Natali Gulbahce
- Department of Cellular and Molecular Pharmacology, University of California 1700, 4th Street, Byers Hall 308D, San Francisco, CA 94158, USA
| | - Frédéric Baribaud
- Janssen Research & Development, Inc., 1400 McKean Road, Spring House, PA 19477, USA
| | - Joel Tocker
- Janssen Research & Development, Inc., 1400 McKean Road, Spring House, PA 19477, USA
| | - Radu Dobrin
- Janssen Research & Development, Inc., 1400 McKean Road, Spring House, PA 19477, USA
| | - Elliot Barnathan
- Janssen Research & Development, Inc., 1400 McKean Road, Spring House, PA 19477, USA
| | - Hao Liu
- Janssen Research & Development, Inc., 1400 McKean Road, Spring House, PA 19477, USA
| | - Reynold A Panettieri
- Pulmonary Allergy and Critical Care Division, Department of Medicine, University of Pennsylvania, 125 South 31st Street, TRL Suite 1200, Philadelphia, PA 19104, USA
| | - Kelan G Tantisira
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Weiliang Qiu
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Benjamin A Raby
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Edwin K Silverman
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Marc Vidal
- Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
| | - Scott T Weiss
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Albert-László Barabási
- Center for Complex Networks Research, Department of Physics, Northeastern University, Boston, MA 02115, USA Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA Department of Theoretical Physics, Budapest University of Technology and Economics, H1111, Budapest, Hungary Center for Network Science, Central European University, Nador u. 9, 1051 Budapest, Hungary
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Peprah E, Xu H, Tekola-Ayele F, Royal CD. Genome-wide association studies in Africans and African Americans: expanding the framework of the genomics of human traits and disease. Public Health Genomics 2014; 18:40-51. [PMID: 25427668 DOI: 10.1159/000367962] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2014] [Accepted: 08/29/2014] [Indexed: 01/11/2023] Open
Abstract
Genomic research is one of the tools for elucidating the pathogenesis of diseases of global health relevance and paving the research dimension to clinical and public health translation. Recent advances in genomic research and technologies have increased our understanding of human diseases, genes associated with these disorders, and the relevant mechanisms. Genome-wide association studies (GWAS) have proliferated since the first studies were published several years ago and have become an important tool in helping researchers comprehend human variation and the role genetic variants play in disease. However, the need to expand the diversity of populations in GWAS has become increasingly apparent as new knowledge is gained about genetic variation. Inclusion of diverse populations in genomic studies is critical to a more complete understanding of human variation and elucidation of the underpinnings of complex diseases. In this review, we summarize the available data on GWAS in recent African ancestry populations within the western hemisphere (i.e. African Americans and peoples of the Caribbean) and continental African populations. Furthermore, we highlight ways in which genomic studies in populations of recent African ancestry have led to advances in the areas of malaria, HIV, prostate cancer, and other diseases. Finally, we discuss the advantages of conducting GWAS in recent African ancestry populations in the context of addressing existing and emerging global health conditions.
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Wang W, Xu S, Yin M, Jin ZG. Essential roles of Gab1 tyrosine phosphorylation in growth factor-mediated signaling and angiogenesis. Int J Cardiol 2014; 181:180-4. [PMID: 25528308 DOI: 10.1016/j.ijcard.2014.10.148] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2014] [Revised: 09/08/2014] [Accepted: 10/18/2014] [Indexed: 12/16/2022]
Abstract
Growth factors and their downstream receptor tyrosine kinases (RTKs) mediate a number of biological processes controlling cell function. Adaptor (docking) proteins, which consist exclusively of domains and motifs that mediate molecular interactions, link receptor activation to downstream effectors. Recent studies have revealed that Grb2-associated-binders (Gab) family members (including Gab1, Gab2, and Gab3), when phosphorylated on tyrosine residues, provide binding sites for multiple effector proteins, such as Src homology-2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2) and phosphatidylinositol 3-kinase (PI3K) regulatory subunit p85, thereby playing important roles in transducing RTKs-mediated signals into pathways with diversified biological functions. Here, we provide an up-to-date overview on the domain structure and biological functions of Gab1, the most intensively studied Gab family protein, in growth factor signaling and biological functions, with a special focus on angiogenesis.
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Affiliation(s)
- Weiye Wang
- Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, 14642, USA
| | - Suowen Xu
- Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, 14642, USA
| | - Meimei Yin
- Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, 14642, USA
| | - Zheng Gen Jin
- Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, 14642, USA.
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25
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Hu S, Zhang Y, Yu Y, Jin D, Zhang X, Gu S, Jia H, Chen X, Zhang Z, Jin Q, Ke Y, Liu H. Growth factor receptor bound protein 2-associated binder 2, a scaffolding adaptor protein, negatively regulates host immunity against tuberculosis. Am J Respir Cell Mol Biol 2014; 51:575-85. [PMID: 24805943 DOI: 10.1165/rcmb.2013-0329oc] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Cell-mediated immunity is indispensable for host protection against tuberculosis (TB). Growth factor receptor bound protein 2-associated binder (Gab) 2, a scaffolding adaptor protein, negatively regulates signaling pathways critical for T cell-mediated immunity. We sought to investigate the clinical significance and immunological role of Gab2 in Mycobacterium tuberculosis infection. We evaluated Gab2 protein and messenger RNA (mRNA) expression in human patients with pulmonary TB and determined the correlation of the mRNA expression pattern with antigen-specific IFN-γ secretion. Subsequently, we carried out M. tuberculosis infection in Gab2-deficient and wild-type control mice to explore the immunological role of Gab2 by examining bacterial load, histological changes, cytokine secretion, and gene expression of immune-associated transcription factors. mRNA levels of Gab2 and its correlated family member, Gab1, were markedly decreased in untreated patients with pulmonary TB compared with healthy control subjects. Importantly, this decreased Gab2 expression to normal levels after bacterial load in the patient's sputum became undetectable under the standard anti-TB treatment, which negatively correlated with the level of M. tuberculosis antigen-specific IFN-γ secretion. In the M. tuberculosis infection mouse model, infected Gab2-deficient mice exhibited decreased bacterial load and milder lung pathological damage compared with infected wild-type mice, accompanied by decreased production of IL-2, IL-6, and granulocyte/macrophage colony-stimulating factor proinflammatory cytokines, and an increased T-cell-specific T-box transcription factor/GATA binding protein 3 expression ratio. Overall, our study indicates that down-regulation of Gab2 relates to a protective function during M. tuberculosis infection, revealing a potential negative regulatory role for Gab2 in immunity to TB.
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MESH Headings
- Adaptor Proteins, Signal Transducing/genetics
- Adaptor Proteins, Signal Transducing/metabolism
- Animals
- Bacterial Load
- Case-Control Studies
- Disease Models, Animal
- GATA3 Transcription Factor/metabolism
- Host-Pathogen Interactions
- Humans
- Immunity, Cellular
- Inflammation Mediators/metabolism
- Lung/immunology
- Lung/metabolism
- Lung/pathology
- Lung/virology
- Mice
- Mice, Knockout
- Mycobacterium tuberculosis/immunology
- Mycobacterium tuberculosis/pathogenicity
- Phosphoproteins/deficiency
- Phosphoproteins/genetics
- Phosphoproteins/metabolism
- RNA, Messenger/metabolism
- TCF Transcription Factors/metabolism
- Time Factors
- Tuberculosis, Pulmonary/genetics
- Tuberculosis, Pulmonary/immunology
- Tuberculosis, Pulmonary/metabolism
- Tuberculosis, Pulmonary/pathology
- Tuberculosis, Pulmonary/prevention & control
- Tuberculosis, Pulmonary/virology
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Affiliation(s)
- Shizong Hu
- 1 Ministry of Health (MOH) Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
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26
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Seda V, Mraz M. B-cell receptor signalling and its crosstalk with other pathways in normal and malignant cells. Eur J Haematol 2014; 94:193-205. [PMID: 25080849 DOI: 10.1111/ejh.12427] [Citation(s) in RCA: 141] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/24/2014] [Indexed: 12/13/2022]
Abstract
The physiology of B cells is intimately connected with the function of their B-cell receptor (BCR). B-cell lymphomas frequently (dys)regulate BCR signalling and thus take advantage of this pre-existing pathway for B-cell proliferation and survival. This has recently been underscored by clinical trials demonstrating that small molecules (fosfamatinib, ibrutinib, idelalisib) inhibiting BCR-associated kinases (SYK, BTK, PI3K) have an encouraging clinical effect. Here we describe the current knowledge of the specific aspects of BCR signalling in diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, chronic lymphocytic leukaemia (CLL) and normal B cells. Multiple factors can contribute to BCR pathway (dys)regulation in these malignancies and the activation of 'chronic' or 'tonic' BCR signalling. In lymphoma B cells, the balance of initiation, amplitude and duration of BCR activation can be influenced by a specific immunoglobulin structure, the expression and mutations of adaptor molecules (like GAB1, BLNK, GRB2, CARD11), the activity of kinases (like LYN, SYK, PI3K) or phosphatases (like SHIP-1, SHP-1 and PTEN) and levels of microRNAs. We also discuss the crosstalk of BCR with other signalling pathways (NF-κB, adhesion through integrins, migration and chemokine signalling) to emphasise that the 'BCR inhibitors' target multiple pathways interconnected with BCR, which might explain some of their clinical activity.
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Affiliation(s)
- Vaclav Seda
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic
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27
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Combined detection of Gab1 and Gab2 expression predicts clinical outcome of patients with glioma. Med Oncol 2014; 31:77. [PMID: 24998422 DOI: 10.1007/s12032-014-0077-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2014] [Accepted: 06/12/2014] [Indexed: 10/25/2022]
Abstract
Grb2-associated binder 1 (Gab1) and Gab2 play important roles in cancer cell signaling. In particular, it has been demonstrated that the upregulation of Gab2 may be correlated with the World Health Organization (WHO) grade of gliomas and that patients with high Gab2 expression levels exhibited shorter survival time. However, the prognostic value of combined expression of Gab1 and Gab2 has not been explored. Gab1 and Gab2 expression in human gliomas and non-neoplastic brain tissues was measured by immunohistochemistry. Both the expression levels of Gab1 and Gab2 proteins in glioma tissues were significantly higher than those in non-neoplastic brain tissues (both P < 0.001). In addition, the overexpression of Gab1 and Gab2 proteins were both significantly associated with advanced WHO grades (both P < 0.001) and low KPS (both P = 0.01). Moreover, the overall survival of patients with high Gab1 protein expression or high Gab2 protein expression was obviously lower than those with low expressions (both P < 0.001). Notably, glioma patients with combined overexpression of Gab1 and Gab2 proteins (Gab1-high/Gab2-high) had shortest overall survival (P < 0.001). Furthermore, multivariate analysis showed that Gab1 expression (P = 0.01), Gab2 expression (P = 0.02), and combined expression of Gab1 and Gab2 (Gab1/Gab2, P = 0.006) were all independent prognostic factors for overall survival in glioma patients. Gab1 and Gab2 proteins are differentially expressed in glioma patients and closely correlated with the biological behavior of this malignancy. Combination of Gab1 and Gab2 expression may represent a promising biomarker for prognostication of human gliomas.
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28
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miR-150 influences B-cell receptor signaling in chronic lymphocytic leukemia by regulating expression of GAB1 and FOXP1. Blood 2014; 124:84-95. [PMID: 24787006 DOI: 10.1182/blood-2013-09-527234] [Citation(s) in RCA: 120] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
We examined the microRNAs (miRNAs) expressed in chronic lymphocytic leukemia (CLL) and identified miR-150 as the most abundant, but with leukemia cell expression levels that varied among patients. CLL cells that expressed ζ-chain-associated protein of 70 kDa (ZAP-70) or that used unmutated immunoglobulin heavy chain variable (IGHV) genes, each had a median expression level of miR-150 that was significantly lower than that of ZAP-70-negative CLL cells or those that used mutated IGHV genes. In samples stratified for expression of miR-150, CLL cells with low-level miR-150 expressed relatively higher levels of forkhead box P1 (FOXP1) and GRB2-associated binding protein 1 (GAB1), genes with 3' untranslated regions having evolutionary-conserved binding sites for miR-150. High-level expression of miR-150 could repress expression of these genes, which encode proteins that enhance B-cell receptor signaling, a putative CLL-growth/survival signal. Also, high-level expression of miR-150 was a significant independent predictor of longer treatment-free survival or overall survival, whereas an inverse association was observed for high-level expression of GAB1 or FOXP1 for overall survival. This study demonstrates that expression of miR-150 can influence the relative expression of GAB1 and FOXP1 and the signaling potential of the B-cell receptor, thereby possibly accounting for the noted association of expression of miR-150 and disease outcome.
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29
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Zhan A, Xu X, Chen L, Wang X, Yanfeng X, Dan W, Zhan Y, Shi Q. Decreased expression of Gab2 in patients with temporal lobe epilepsy and pilocarpine-induced rat model. Synapse 2013; 68:168-77. [PMID: 24327320 DOI: 10.1002/syn.21725] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2013] [Revised: 11/24/2013] [Accepted: 12/04/2013] [Indexed: 12/30/2022]
Abstract
Growth factor receptor bound protein-2 associated binding protein-2 (Gab2) is widely expressed in the central nervous system, and participates in multiple signaling pathways. Recent studies showed that Gab2 was involved in the pathogenesis of Alzheimer's disease (AD). Gab2 reduces tau phosphorylation levels and is associated with cellular apoptosis and differentiation. However, whether Gab2 was also involved in the pathogenesis of epilepsy, remains unknown. This study aimed to investigate the expression pattern of Gab2 protein in brains with temporal lobe epilepsy (TLE) and in pilocarpine-induced rat model of TLE. Western blot, immunohistochemistry, and immunofluorescence were used to assess the location and the expression level of Gab2 in the neocortex of the temporal lobe in patients with TLE and in rat model of epilepsy. Results showed that Gab2 protein was expressed mainly in the membranes and cytoplasm of neurons in the cortex and hippocampus. Gab2 protein expression was remarkably reduced in temporal neocortex of TLE patients. In hippocampus and adjacent cortex in rat epilepsy model, Gab2 expression was decreased at different time points after kindling compared with the controls, and the lowest level of Gab2 expression occurred at 1 week. Thus, significant reductions of Gab2 protein in both TLE patients and epilepsy rats suggest that Gab2 may play an important role in the pathogenesis of TLE.
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Affiliation(s)
- Ao Zhan
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
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30
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Jin C, Wu CZ, Liu X, Zhang F, Tian L, Yuan J, Wang G, Cheng Z. GAB2 polymorphism rs2373115 confers susceptibility to sporadic Alzheimer's disease. Neurosci Lett 2013; 556:216-20. [DOI: 10.1016/j.neulet.2013.10.036] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2013] [Revised: 09/30/2013] [Accepted: 10/12/2013] [Indexed: 11/15/2022]
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31
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Tamari M, Tanaka S, Hirota T. Genome-wide association studies of allergic diseases. Allergol Int 2013; 62:21-28. [PMID: 23439055 DOI: 10.2332/allergolint.13-rai-0539] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2013] [Indexed: 12/12/2022] Open
Abstract
Allergic diseases are complex diseases caused by a combination of genetic and environmental factors. To determine the genetic components of these diseases and to discover the genes and cellular pathways underlying them, a large number of genetic studies have been conducted. Progress in genetics enables us to conduct genome-wide association studies (GWASs), which is a comprehensive and unbiased approach to identify susceptibility loci for multifactorial diseases. Recent GWASs have convincingly detected a large number of loci associated with allergic diseases. Candidate genes in the susceptibility loci suggest roles for epithelial barrier functions, innate-adaptive immunity, IL-1 family signaling, regulatory T cells and the vitamin D pathway in the pathogenesis of allergic diseases. Interestingly, the IL1RL1, HLA, IL13 and C11orf30 regions are overlapping susceptibility loci among atopic dermatitis and asthma or allergic rhinitis. Although a more complete collection of associated genes and pathways is needed, biologic insights revealed by GWASs improve our understanding of the pathophysiology of human allergic diseases and contribute to the development of better treatment and preventive strategies.
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Affiliation(s)
- Mayumi Tamari
- Laboratory for Respiratory Diseases, Center for Genomic Medicine, Institute of Physical and Chemical Research (RIKEN), Kanagawa, Japan.
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32
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Le Goff A, Ji Z, Leclercq B, Bourette RP, Mougel A, Guerardel C, de Launoit Y, Vicogne J, Goormachtigh G, Fafeur V. Anti-apoptotic role of caspase-cleaved GAB1 adaptor protein in hepatocyte growth factor/scatter factor-MET receptor protein signaling. J Biol Chem 2012; 287:35382-35396. [PMID: 22915589 PMCID: PMC3471683 DOI: 10.1074/jbc.m112.409797] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2012] [Revised: 08/20/2012] [Indexed: 11/06/2022] Open
Abstract
The GRB2-associated binder 1 (GAB1) docking/scaffold protein is a key mediator of the MET-tyrosine kinase receptor activated by hepatocyte growth factor/scatter factor (HGF/SF). Activated MET promotes recruitment and tyrosine phosphorylation of GAB1, which in turn recruits multiple proteins and mediates MET signaling leading to cell survival, motility, and morphogenesis. We previously reported that, without its ligand, MET is a functional caspase target during apoptosis, allowing the generation of a p40-MET fragment that amplifies apoptosis. In this study we established that GAB1 is also a functional caspase target by evidencing a caspase-cleaved p35-GAB1 fragment that contains the MET binding domain. GAB1 is cleaved by caspases before MET, and the resulting p35-GAB1 fragment is phosphorylated by MET upon HGF/SF binding and can interact with a subset of GAB1 partners, PI3K, and GRB2 but not with SHP2. This p35-GAB1 fragment favors cell survival by maintaining HGF/SF-induced MET activation of AKT and by hindering p40-MET pro-apoptotic function. These data demonstrate an anti-apoptotic role of caspase-cleaved GAB1 in HGF/SF-MET signaling.
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Affiliation(s)
- Arnaud Le Goff
- CNRS UMR 8161, Institut de Biologie de Lille, Université Lille-Nord de France, Institut Pasteur de Lille, IFR142, Lille, France
| | - Zongling Ji
- CNRS UMR 8161, Institut de Biologie de Lille, Université Lille-Nord de France, Institut Pasteur de Lille, IFR142, Lille, France; Faculty of Life Sciences, C2222 Michael Smith Building, University of Manchester, Manchester, United Kingdom
| | - Bérénice Leclercq
- CNRS UMR 8161, Institut de Biologie de Lille, Université Lille-Nord de France, Institut Pasteur de Lille, IFR142, Lille, France
| | - Roland P Bourette
- CNRS UMR 8161, Institut de Biologie de Lille, Université Lille-Nord de France, Institut Pasteur de Lille, IFR142, Lille, France
| | - Alexandra Mougel
- CNRS UMR 8161, Institut de Biologie de Lille, Université Lille-Nord de France, Institut Pasteur de Lille, IFR142, Lille, France
| | - Cateline Guerardel
- CNRS UMR 8161, Institut de Biologie de Lille, Université Lille-Nord de France, Institut Pasteur de Lille, IFR142, Lille, France
| | - Yvan de Launoit
- CNRS UMR 8161, Institut de Biologie de Lille, Université Lille-Nord de France, Institut Pasteur de Lille, IFR142, Lille, France
| | - Jérôme Vicogne
- CNRS UMR 8161, Institut de Biologie de Lille, Université Lille-Nord de France, Institut Pasteur de Lille, IFR142, Lille, France
| | - Gautier Goormachtigh
- CNRS UMR 8161, Institut de Biologie de Lille, Université Lille-Nord de France, Institut Pasteur de Lille, IFR142, Lille, France
| | - Véronique Fafeur
- CNRS UMR 8161, Institut de Biologie de Lille, Université Lille-Nord de France, Institut Pasteur de Lille, IFR142, Lille, France.
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Abstract
Adaptor or scaffolding proteins mediate protein-protein interactions that drive the formation of protein complexes. Grb2-associated binding protein 2 (GAB2) scaffolding protein is an intermediary molecule that links plasma membrane receptor signaling including receptor tyrosine kinases with the downstream effectors, such as protein tyrosine phosphatase, nonreceptor type 11 (SHP2), p85 subunit of phosphoinositide-3 kinase (PI3-K), phospholipase C-gamma 1 (PLC-γ), v-crk sarcoma virus CT10 (CRK), Src homology 2 domain containing transforming protein 1 (SHC), and SH2 containing inositol phosphatase (SHIP). Although, well described in signal transduction, its role in cancer has recently been emerging especially in leukemia, breast and ovarian cancer, and melanoma. GAB2 is essential for two major signal transduction pathways in cancer, the PI3-K-AKT and extracellular signal-regulated kinase (ERK) signaling pathways, and thus regulates a number of key cellular processes. This review focuses on structure and function of GAB2, its regulatory proteins, emerging role in cancer, and potential as a therapeutic target.
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Affiliation(s)
- Sarah J Adams
- Department of Dermatology, Columbia University Medical Center, New York 10032, USA
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34
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Siddle K. Molecular basis of signaling specificity of insulin and IGF receptors: neglected corners and recent advances. Front Endocrinol (Lausanne) 2012; 3:34. [PMID: 22649417 PMCID: PMC3355962 DOI: 10.3389/fendo.2012.00034] [Citation(s) in RCA: 111] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2011] [Accepted: 02/13/2012] [Indexed: 12/15/2022] Open
Abstract
Insulin and insulin-like growth factor (IGF) receptors utilize common phosphoinositide 3-kinase/Akt and Ras/extracellular signal-regulated kinase signaling pathways to mediate a broad spectrum of "metabolic" and "mitogenic" responses. Specificity of insulin and IGF action in vivo must in part reflect expression of receptors and responsive pathways in different tissues but it is widely assumed that it is also determined by the ligand binding and signaling mechanisms of the receptors. This review focuses on receptor-proximal events in insulin/IGF signaling and examines their contribution to specificity of downstream responses. Insulin and IGF receptors may differ subtly in the efficiency with which they recruit their major substrates (IRS-1 and IRS-2 and Shc) and this could influence effectiveness of signaling to "metabolic" and "mitogenic" responses. Other substrates (Grb2-associated binder, downstream of kinases, SH2Bs, Crk), scaffolds (RACK1, β-arrestins, cytohesins), and pathways (non-receptor tyrosine kinases, phosphoinositide kinases, reactive oxygen species) have been less widely studied. Some of these components appear to be specifically involved in "metabolic" or "mitogenic" signaling but it has not been shown that this reflects receptor-preferential interaction. Very few receptor-specific interactions have been characterized, and their roles in signaling are unclear. Signaling specificity might also be imparted by differences in intracellular trafficking or feedback regulation of receptors, but few studies have directly addressed this possibility. Although published data are not wholly conclusive, no evidence has yet emerged for signaling mechanisms that are specifically engaged by insulin receptors but not IGF receptors or vice versa, and there is only limited evidence for differential activation of signaling mechanisms that are common to both receptors. Cellular context, rather than intrinsic receptor activity, therefore appears to be the major determinant of whether responses to insulin and IGFs are perceived as "metabolic" or "mitogenic."
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Affiliation(s)
- Kenneth Siddle
- University of Cambridge Metabolic Research Laboratories and Department of Clinical Biochemistry, Institute of Metabolic Science, Addenbrooke's Hospital Cambridge, UK.
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35
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Receptor Kinase Interactions: Complexity of Signalling. SIGNALING AND COMMUNICATION IN PLANTS 2012. [DOI: 10.1007/978-3-642-23044-8_9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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Kanai A, Suzuki K, Tanimoto K, Mizushima-Sugano J, Suzuki Y, Sugano S. Characterization of STAT6 target genes in human B cells and lung epithelial cells. DNA Res 2011; 18:379-92. [PMID: 21828071 PMCID: PMC3190958 DOI: 10.1093/dnares/dsr025] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Using ChIP Seq, we identified 556 and 467 putative STAT6 target sites in the Burkitt's lymphoma cell line Ramos and in the normal lung epithelial cell line BEAS2B, respectively. We also examined the positions and expression of transcriptional start sites (TSSs) in these cells using our TSS Seq method. We observed that 44 and 132 genes in Ramos and BEAS2B, respectively, had STAT6 binding sites in proximal regions of their previously reported TSSs that were up-regulated at the transcriptional level. In addition, 406 and 109 of the STAT6 target sites in Ramos and BEAS2B, respectively, were located in proximal regions of previously uncharacterized TSSs. The target genes identified in Ramos and BEAS2B cells in this study and in Th2 cells in previous studies rarely overlapped and differed in their identity. Interestingly, ChIP Seq analyses of histone modifications and RNA polymerase II revealed that chromatin formed an active structure in regions surrounding the STAT6 binding sites; this event also frequently occurred in different cell types, although neither STAT6 binding nor TSS induction was observed. The rough landscape of STAT6-responsive sites was found to be shaped by chromatin structure, but distinct cellular responses were mainly mediated by distinct sets of transcription factors.
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Affiliation(s)
- Akinori Kanai
- Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwashi, Chiba 277-8562, Japan
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Genome-wide association study identifies three new susceptibility loci for adult asthma in the Japanese population. Nat Genet 2011; 43:893-6. [PMID: 21804548 DOI: 10.1038/ng.887] [Citation(s) in RCA: 254] [Impact Index Per Article: 18.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2011] [Accepted: 06/16/2011] [Indexed: 02/06/2023]
Abstract
Bronchial asthma is a common inflammatory disease caused by the interaction of genetic and environmental factors. Through a genome-wide association study and a replication study consisting of a total of 7,171 individuals with adult asthma (cases) and 27,912 controls in the Japanese population, we identified five loci associated with susceptibility to adult asthma. In addition to the major histocompatibility complex and TSLP-WDR36 loci previously reported, we identified three additional loci: a USP38-GAB1 locus on chromosome 4q31 (combined P = 1.87 × 10(-12)), a locus on chromosome 10p14 (P = 1.79 × 10(-15)) and a gene-rich region on chromosome 12q13 (P = 2.33 × 10(-13)). We observed the most significant association with adult asthma at rs404860 in the major histocompatiblity complex region (P = 4.07 × 10(-23)), which is close to rs2070600, a SNP previously reported for association with FEV(1)/FVC in genome-wide association studies for lung function. Our findings offer a better understanding of the genetic contribution to asthma susceptibility.
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38
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Interferon-γ-induced increases in intestinal epithelial macromolecular permeability requires the Src kinase Fyn. J Transl Med 2011; 91:764-77. [PMID: 21321534 DOI: 10.1038/labinvest.2010.208] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Interferon-γ (IFNγ) is an important immunoregulatory cytokine that can also decrease intestinal epithelial barrier function. Little is known about the intracellular signalling events immediately subsequent to IFNγ/IFNγ receptor interaction that mediate increases in epithelial permeability; data that could be used to ablate this effect of IFNγ while leaving its immunostimulatory effects intact. This study assessed the potential involvement of Src family kinases in IFNγ-induced increases in epithelial permeability using confluent filter-grown monolayers of the human colon-derived T84 epithelial cell line. Inhibition of Src kinase with the pharmacologic PP1 and use of Fyn kinase-specific siRNA significantly reduced IFNγ-induced increases in epithelial permeability as gauged by translocation of noninvasive E. coli (HB101 strain) and flux of horseradish peroxidase (HRP) across monolayers of T84 cells. However, the drop in transepithelial resistance elicited by IFNγ was not affected by either treatment. Immunoblotting revealed that IFNγ activated the transcription factor STAT5 in T84 cells, and immunoprecipitation studies identified an IFNγ-inducible interaction between STAT5b and the PI3K regulatory subunit p85α through formation of a complex requiring the adaptor molecule Gab2. siRNA targeting STAT5b and Gab2 reduced IFNγ-induced increases in epithelial permeability and phosphorylation of PI3K(p85α). PP1 and Fyn siRNA reduced IFNγ-induced PI3K activity (indicated by decreased phospho-Akt) and the formation of the STAT5b/PI3K(p85α) complex. Collectively, the results suggest the formation of a Fyn-dependent STAT5b/Gab2/PI3K complex that links IFNγ to PI3K signalling and the regulation of macromolecular permeability in a model enteric epithelium.
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Zhong XL, Yu JT, Hou GY, Xing YY, Jiang H, Li Y, Tan L. Common variant in GAB2 is associated with late-onset Alzheimer's disease in Han Chinese. Clin Chim Acta 2011; 412:446-9. [DOI: 10.1016/j.cca.2010.11.022] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2010] [Revised: 11/05/2010] [Accepted: 11/16/2010] [Indexed: 12/23/2022]
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C terminus of the P2X7 receptor: treasure hunting. Purinergic Signal 2011; 7:7-19. [PMID: 21484094 DOI: 10.1007/s11302-011-9215-1] [Citation(s) in RCA: 103] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2010] [Accepted: 01/05/2011] [Indexed: 12/21/2022] Open
Abstract
P2X receptor (P2XR) is a family of the ATP-gated ion channel family and can permeabilize the plasma membrane to small cations such as potassium, sodium, and calcium, resulting in cellular depolarization. There are seven P2XR that have been described and cloned, with 45% identity in amino acid sequence. Each P2X receptors has two transmembrane domains that are separated by an extracellular loop and an intracellular N and C terminus. Unlike the other P2X receptors, the P2X7R has a larger C terminus with an extra 200 amino acid residues compared with the other receptors. The C terminus of the P2X7R has been implicated in regulating receptor function including signaling pathway activation, cellular localization, protein-protein interactions, and post-translational modification (PTM). In the present review, we discuss the role of the P2X7R C terminus in regards to receptor function, describe the specific domains and motifs found therein and compare the C terminus sequence with others proteins to discover predicted domains or sites of PTM.
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Felici A, Giubellino A, Bottaro DP. Gab1 mediates hepatocyte growth factor-stimulated mitogenicity and morphogenesis in multipotent myeloid cells. J Cell Biochem 2010; 111:310-21. [PMID: 20506405 PMCID: PMC3393599 DOI: 10.1002/jcb.22695] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Hepatocyte growth factor (HGF)-stimulated mitogenesis, motogenesis and morphogenesis in various cell types begins with activation of the Met receptor tyrosine kinase and the recruitment of intracellular adaptors and kinase substrates. The adapter protein Gab1 is a critical effector and substrate of activated Met, mediating morphogenesis, among other activities, in epithelial cells. To define its role downstream of Met in hematopoietic cells, Gab1 was expressed in the HGF-responsive, Gab1-negative murine myeloid cell line 32D. Interestingly, the adhesion and motility of Gab1-expressing cells were significantly greater than parental cells, independent of growth factor treatment. Downstream of activated Met, Gab1 expression was specifically associated with rapid Shp-2 recruitment and activation, increased mitogenic potency, suppression of GATA-1 expression and concomitant upregulation of GATA-2 transcription. In addition to enhanced proliferation, continuous culture of Gab1-expressing 32D cells in HGF resulted in cell attachment, filopodia extension and phenotypic changes suggestive of monocytic differentiation. Our results suggest that in myeloid cells, Gab1 is likely to enhance HGF mitogenicity by coupling Met to Shp-2 and GATA-2 expression, thereby potentially contributing to normal myeloid differentiation as well as oncogenic transformation.
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Affiliation(s)
| | | | - Donald P. Bottaro
- Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1501, USA
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42
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Zhang TT, Li H, Cheung SM, Costantini JL, Hou S, Al-Alwan M, Marshall AJ. Phosphoinositide 3-kinase-regulated adapters in lymphocyte activation. Immunol Rev 2010; 232:255-72. [PMID: 19909369 DOI: 10.1111/j.1600-065x.2009.00838.x] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Signaling via phosphoinositide 3-kinases (PI3Ks) has emerged as a central component of lymphocyte activation via immunoreceptors, costimulatory receptors, cytokine receptors, and chemokine receptors. The discovery of phosphoinositide-binding pleckstrin homology (PH) domains has substantially increased understanding of how PI3Ks activate cellular responses. Accumulating evidence indicates that PH-domain containing adapter molecules provide important links between PI3K and lymphocyte function. Here, we review data on PI3K-regulated adapter proteins of the Grb-associated binder (GAB), Src kinase-associated phosphoprotein (SKAP), and B-lymphocyte adapter molecule of 32 kDa (Bam32)/ dual-adapter for phosphotyrosine and 3-phosphoinositides (DAPP)/TAPP families, with a focus on the latter group. Current data support the model that recruitment of these adapters to the plasma membrane of activated lymphocytes is driven by the phosphoinositides phosphatidylinositol-3,4,5-tris-phosphate and phosphatidylinositol-3,4-bisphosphate, generated through the action of PI3Ks and under the regulatory control of lipid phosphatases Src homology 2 domain-containing inositol phosphatase (SHIP), phosphatase and tensin homolog, and inositol polyphosphate 4-phosphatase. At the plasma membrane, these adapters serve to assemble distinct protein complexes. Bam32/DAPP1 and SKAPs function to promote activation of monomeric guanosine triphosphatases, including Rac and Rap, and promote integrin activation, lymphocyte adhesion to matrix proteins, and cell:cell interactions between B and T lymphocytes. GABs can provide feedforward amplification or feedback inhibition of PI3K signaling. Current work is further defining the molecular interactions driven by these molecules and identifying the functions of TAPP adapters, which also appear to be involved in lymphocyte adhesion and are specific effectors downstream of the SHIP product phosphatidylinositol-3,4-bisphosphate.
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Affiliation(s)
- Ting-Ting Zhang
- Department of Immunology, University of Manitoba, Winnipeg, MB, Canada
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43
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Pan XL, Ren RJ, Wang G, Tang HD, Chen SD. The Gab2 in signal transduction and its potential role in the pathogenesis of Alzheimer's disease. Neurosci Bull 2010; 26:241-6. [PMID: 20502503 PMCID: PMC5560293 DOI: 10.1007/s12264-010-1109-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2009] [Accepted: 02/24/2010] [Indexed: 12/29/2022] Open
Abstract
The growth factor receptor-bound protein 2 (Grb2)-associated binder (Gab) proteins are intracellular scaffolding/docking molecules, and participate in multiple signaling pathways, usually acting as the downstream effector of protein-tyrosine kinases (PTKs)-triggered signal transduction pathway. When phosphorylated by PTKs, Gab proteins can recruit several signaling molecules (p85, SHP2, and Crk), and subsequently activate multiple transmitting signals that are critical for cell growth, survival, differentiation and apoptosis. Recently, it has been reported that Gab2 polymorphism is associated with the increase in the risk of Alzheimer's disease (AD) and is involved in the pathogenesis of AD. This review mainly focuses on the structure and function of Gab2 protein and its role in the pathogenesis of AD.
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Affiliation(s)
- Xiao-Ling Pan
- Department of Neurology and Neuroscience Institute, Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200025 China
| | - Ru-Jing Ren
- Department of Neurology and Neuroscience Institute, Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200025 China
| | - Gang Wang
- Department of Neurology and Neuroscience Institute, Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200025 China
| | - Hui-Dong Tang
- Department of Neurology and Neuroscience Institute, Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200025 China
| | - Sheng-Di Chen
- Department of Neurology and Neuroscience Institute, Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200025 China
- Laboratory of Neurodegenerative Diseases, Institute of Health Science, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences and Shanghai Jiaotong University School of Medicine, Shanghai, 200025 China
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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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Abstract
Since the 1990s, the genetics of Alzheimer disease (AD) has been an active area of research. The identification of deterministic mutations in the APP, PSEN1, and PSEN2 genes responsible for early-onset autosomal dominant familial forms of AD led to a better understanding of the pathophysiology of this disease. In the past decade, the plethora of candidate genes and regions emerging from genetic linkage and smaller-scale association studies yielded intriguing 'hits' that have often proven difficult to replicate consistently. In the last two years, 11 published genome-wide association studies (GWASs) in AD confirmed the universally accepted role of APOE as a genetic risk factor for late-onset AD as well as generating additional candidate genes that require confirmation. It is unclear whether GWASs, though a promising novel approach in the genetics of complex diseases, can help explain most of the underlying genetic risk for AD. This review provides a brief summary of the genetic studies in AD preceding the GWAS era, with the main focus on the findings from recent GWASs. Potential approaches that could provide further insight into the genetics of AD in the post-GWAS era are also discussed.
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Affiliation(s)
- Nilüfer Ertekin-Taner
- Mayo Clinic Florida, Departments of Neurology and Neuroscience, 4500 San Pablo Road, Birdsall 210, Jacksonville, FL 32224 USA.
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Bocanegra M, Bergamaschi A, Kim YH, Miller MA, Rajput AB, Kao J, Langerød A, Han W, Noh DY, Jeffrey SS, Huntsman DG, Børresen-Dale AL, Pollack JR. Focal amplification and oncogene dependency of GAB2 in breast cancer. Oncogene 2009; 29:774-9. [PMID: 19881546 DOI: 10.1038/onc.2009.364] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
DNA amplifications in breast cancer are frequent on chromosome 11q, in which multiple driver oncogenes likely reside in addition to cyclin D1 (CCND1). One such candidate, the scaffolding adapter protein, GRB2-associated binding protein 2 (GAB2), functions in ErbB signaling and was recently shown to enhance mammary epithelial cell proliferation, and metastasis of ERBB2 (HER2/neu)-driven murine breast cancer. However, the amplification status and function of GAB2 in the context of amplification remain undefined. In this study, by genomic profiling of 172 breast tumors, and fluorescence in situ hybridization validation in an independent set of 210 scorable cases, we observed focal amplification spanning GAB2 (11q14.1) independent of CCND1 (11q13.2) amplification, consistent with a driver role. Further, small interfering RNA (siRNA)-mediated knockdown of GAB2 in breast cancer lines (SUM52, SUM44PE and MDA468) with GAB2 amplification revealed a dependency on GAB2 for cell proliferation, cell-cycle progression, survival and invasion, likely mediated through altered phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling. GAB2 knockdown also reduced proliferation and survival in a cell line (BT474) with ERBB2 amplification, consistent with the possibility that GAB2 can function downstream of ERBB2. Our studies implicate focal amplification of GAB2 in breast carcinogenesis, and underscore an oncogenic role of scaffolding adapter proteins, and a potential new point of therapeutic intervention.
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Affiliation(s)
- M Bocanegra
- Department of Pathology, Stanford University, Stanford, CA 94305-5176, USA
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Gab1 transduces PI3K-mediated erythropoietin signals to the Erk pathway and regulates erythropoietin-dependent proliferation and survival of erythroid cells. Cell Signal 2009; 21:1775-83. [PMID: 19665053 DOI: 10.1016/j.cellsig.2009.07.013] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2009] [Revised: 07/28/2009] [Accepted: 07/28/2009] [Indexed: 11/23/2022]
Abstract
In this study, we examined the biological functions of Gab1 in erythropoietin receptor (EPOR)-mediated signaling in vivo. Knockdown of Gab1 by the introduction of the Gab1 siRNA expression vector into F-36P human erythroleukemia (F-36P-Gab1-siRNA) cells resulted in a reduction of cell proliferation and survival in response to EPO. EPO-induced activation of Erk1/2 but not of Akt was significantly suppressed in F-36P-Gab1-siRNA cells compared with mock-transfected F-36P cells. The co-immunoprecipitation experiments revealed an EPO-enhanced association of Gab1 with the Grb2-SOS1 complex and SHP-2 in F-36P cells. A selective inhibitor of phosphatidylinositol 3-kinase (PI3K) LY294002 and short interfering RNA (siRNA) duplexes targeting the p85 regulatory subunit of PI3K (p85-siRNA) independently suppressed tyrosine phosphorylation of Gab1; its association with Grb2, SHP-2 and p85; and the activation of Erk in EPO-treated F-36P cells. LY294002 inhibited EPO-induced tyrosine phosphorylation of Gab1 and its association with Grb2 in human primary EPO-sensitive erythroid cells. The co-immunoprecipitation experiments using the Jak inhibitor AG490 or siRNA duplexes targeting Jak2 and in vitro binding experiments demonstrated that Jak2 regulated Gab1-mediated Erk activation through tyrosine phosphorylation of Gab1. Taken together, these results suggest that Gab1 couples PI3K-mediated EPO signals with the Ras/Erk pathway and that Gab1 plays an important role in EPOR-mediated signal transduction involved in the proliferation and survival of erythroid cells.
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Zeke A, Lukács M, Lim WA, Reményi A. Scaffolds: interaction platforms for cellular signalling circuits. Trends Cell Biol 2009; 19:364-74. [PMID: 19651513 PMCID: PMC3073007 DOI: 10.1016/j.tcb.2009.05.007] [Citation(s) in RCA: 116] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2009] [Revised: 05/17/2009] [Accepted: 05/18/2009] [Indexed: 12/12/2022]
Abstract
Scaffold proteins influence cellular signalling by binding to multiple signalling enzymes, receptors or ion channels. Although normally devoid of catalytic activity, they have a big impact on controlling the flow of signalling information. By assembling signalling proteins into complexes, they play the part of signal processing hubs. As we learn more about the way signalling components are linked into natural signalling circuits, researchers are becoming interested in building non-natural signalling pathways to test our knowledge and/or to intentionally reprogram cellular behaviour. In this review, we discuss the role of scaffold proteins as efficient tools for assembling intracellular signalling complexes, both natural and artificial.
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Affiliation(s)
- András Zeke
- Department of Biochemistry, Eötvös Loránd University, Pázmány Péter sétány 1/C, H-1117 Budapest, Hungary
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Caron C, Spring K, Laramée M, Chabot C, Cloutier M, Gu H, Royal I. Non-redundant roles of the Gab1 and Gab2 scaffolding adapters in VEGF-mediated signalling, migration, and survival of endothelial cells. Cell Signal 2009; 21:943-53. [PMID: 19233262 DOI: 10.1016/j.cellsig.2009.02.004] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2008] [Revised: 02/02/2009] [Accepted: 02/10/2009] [Indexed: 01/07/2023]
Abstract
Gab1 was previously described as a positive modulator of Akt, Src, ERK1/2, endothelial cell migration, and capillary formation in response to vascular endothelial growth factor (VEGF). However, its involvement in endothelial cell survival, as well as the potential contribution of the other family member Gab2 to signalling and biological responses remained unknown. Here, we show that Gab2 is tyrosine phosphorylated in a Grb2-dependent manner downstream of activated VEGF receptor-2 (VEGFR2), and that it associates with signalling proteins including PI3K and SHP2, but apparently not with the receptor. Similarly to Gab1, over-expression of Gab2 induces endothelial cell migration in response to VEGF, whereas its depletion using siRNAs results in its reduction. Importantly, depletion of both Gab1 and Gab2 leads to an even greater inhibition of VEGF-induced cell migration. However, contrary to what has been reported for Gab1, the silencing of Gab2 results in increased Src, Akt and ERK1/2 activation, slightly reduced p38 phosphorylation, and up-regulation of Gab1 protein levels. Accordingly, re-expression of Gab2 in Gab2-/- fibroblasts leads to opposite results, suggesting that the modulation of both Gab2 and Gab1 expression in these conditions might contribute to the impaired signalling observed. Consistent with their opposite roles on Akt, the depletion of Gab1, but not of Gab2, results in reduced FOXO1 phosphorylation and VEGF-mediated endothelial cell survival. Mutation of VEGFR2 Y801 and Y1214, which abrogates the phosphorylation of Gab1, also correlates with inhibition of Akt. Altogether, these results underscore the non-redundant and essential roles of Gab1 and Gab2 in endothelial cells, and suggest major contributions of these proteins during in vivo angiogenesis.
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Affiliation(s)
- Christine Caron
- Centre de recherche du Centre Hospitalier de l'Université de Montréal, 1560 rue Sherbrooke est, Montréal, Québec, Canada.
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50
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de la Puerta ML, Trinidad AG, Rodríguez MDC, Bogetz J, Sánchez Crespo M, Mustelin T, Alonso A, Bayón Y. Characterization of new substrates targeted by Yersinia tyrosine phosphatase YopH. PLoS One 2009; 4:e4431. [PMID: 19221593 PMCID: PMC2637541 DOI: 10.1371/journal.pone.0004431] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2008] [Accepted: 12/17/2008] [Indexed: 12/24/2022] Open
Abstract
YopH is an exceptionally active tyrosine phosphatase that is essential for virulence of Yersinia pestis, the bacterium causing plague. YopH breaks down signal transduction mechanisms in immune cells and inhibits the immune response. Only a few substrates for YopH have been characterized so far, for instance p130Cas and Fyb, but in view of YopH potency and the great number of proteins involved in signalling pathways it is quite likely that more proteins are substrates of this phosphatase. In this respect, we show here YopH interaction with several proteins not shown before, such as Gab1, Gab2, p85, and Vav and analyse the domains of YopH involved in these interactions. Furthermore, we show that Gab1, Gab2 and Vav are not dephosphorylated by YopH, in contrast to Fyb, Lck, or p85, which are readily dephosphorylated by the phosphatase. These data suggests that YopH might exert its actions by interacting with adaptors involved in signal transduction pathways, what allows the phosphatase to reach and dephosphorylate its susbstrates.
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Affiliation(s)
| | - Antonio G. Trinidad
- Instituto de Biología y Genética Molecular, CSIC-Universidad de Valladolid, Valladolid, Spain
| | | | - Jori Bogetz
- Program of Inflammation, Inflammatory and Infectious Disease Center, and Program of Signal Transduction, Burnham Institute for Medical Research, La Jolla, California, United States of America
| | - Mariano Sánchez Crespo
- Instituto de Biología y Genética Molecular, CSIC-Universidad de Valladolid, Valladolid, Spain
| | - Tomas Mustelin
- Program of Inflammation, Inflammatory and Infectious Disease Center, and Program of Signal Transduction, Burnham Institute for Medical Research, La Jolla, California, United States of America
| | - Andrés Alonso
- Instituto de Biología y Genética Molecular, CSIC-Universidad de Valladolid, Valladolid, Spain
| | - Yolanda Bayón
- Instituto de Biología y Genética Molecular, CSIC-Universidad de Valladolid, Valladolid, Spain
- * E-mail:
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