• T cell
• T cell-antigen receptor
• experimental autoimmune encephalomyelitis
• signal-transducing adaptor protein-2

• Animals
• Humans
• Mice
• Adaptor Proteins, Signal Transducing/physiology
• Adaptor Proteins, Signal Transducing/metabolism
• Apoptosis
• CD3 Complex
• Cell Adhesion
• Cell Movement
• Chemokine CXCL12/physiology
• Chemokine CXCL12/metabolism
• Encephalomyelitis, Autoimmune, Experimental/immunology
• Encephalomyelitis, Autoimmune, Experimental/etiology
• Inflammation/immunology
• Lymphocyte Activation
• Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/physiology
• Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/metabolism
• Propionibacterium acnes/physiology
• Propionibacterium acnes/immunology
• Receptors, Antigen, T-Cell/physiology
• Receptors, Antigen, T-Cell/metabolism
• Signal Transduction
• T-Lymphocytes/immunology
• ZAP-70 Protein-Tyrosine Kinase/metabolism
• ZAP-70 Protein-Tyrosine Kinase/physiology

• B cells
• Csk
• Lyn
• signal-transducing adaptor protein-2

• Mice
• Animals
• CSK Tyrosine-Protein Kinase/metabolism
• Signal Transduction
• src-Family Kinases/genetics
• src-Family Kinases/metabolism
• Receptors, Antigen, B-Cell/metabolism
• Phosphorylation
• B-Lymphocytes/metabolism
• Mice, Knockout

• PTK6
• colorectal cancer
• tyrosine kinase inhibitors

• glycolysis
• intestinal barrier
• intestinal inflammation
• low-birth-weight
• macrophage

• T cell antigen receptor (TCR)
• T cells
• immune response
• signal transduction
• signal-transducing adaptor protein-2 (STAP-2)

• Breast cancer
• Breast cancer stem cells (BCSCs)
• Breast cancer therapeutics
• STAT inhibitors
• Signal transducer and activator of transcription (STAT)

• Female
• Humans
• Breast Neoplasms/genetics
• Breast Neoplasms/therapy
• Neoplasm Recurrence, Local
• Neoplastic Stem Cells
• Neoplasms, Second Primary
• Carcinogenesis

• F31 CA261027 NCI NIH HHS
• P30 CA012197 NCI NIH HHS
• R01 CA228137 NCI NIH HHS

• IL-33
• Mast cells
• NF-κB
• ST2
• Signal-transducing adaptor molecule-2

• adaptor protein
• immune response
• inflammation
• signal transduction
• signal-transducing adaptor protein (STAP)-2

BReast tumor Kinase (BRK, also known as PTK6) is a non-receptor tyrosine kinase that is highly expressed in breast carcinomas while having low expression in the normal mammary gland, which hints at the oncogenic nature of this kinase in breast cancer. In the past twenty-six years since the discovery of BRK, an increasing number of studies have strived to understand the cellular roles of BRK in breast cancer. Since then, BRK has been found both in vitro and in vivo to activate a multitude of oncoproteins to promote cell proliferation, metastasis, and cancer development. The compelling evidence concerning the oncogenic roles of BRK has also led, since then, to the rapid and exponential development of inhibitors against BRK. This review highlights recent advances in BRK biology in contributing to the “hallmarks of cancer”, as well as BRK's therapeutic significance. Importantly, this review consolidates all known inhibitors of BRK activity and highlights the connection between drug action and BRK-mediated effects. Despite the volume of inhibitors designed against BRK, none have progressed into clinical phase. Understanding the successes and challenges of these inhibitor developments are crucial for the future improvements of new inhibitors that can be clinically relevant.

• Breast tumor kinase (BRK)
• chemical inhibitors
• hallmarks of cancer
• meta-analysis
• molecular inhibitors

Signal transducers and activators of transcription (STATs) mediate essential signaling pathways in different biological processes, including immune responses, hematopoiesis, and neurogenesis. Among the STAT members, STAT3 plays crucial roles in cell proliferation, survival, and differentiation. While STAT3 activation is transient in physiological conditions, STAT3 becomes persistently activated in a high percentage of solid and hematopoietic malignancies (e.g., melanoma, multiple myeloma, breast, prostate, ovarian, and colon cancers), thus contributing to malignant transformation and progression. This makes STAT3 an attractive therapeutic target for cancers. Initial strategies aimed at inhibiting STAT3 functions have focused on blocking the action of its activating kinases or sequestering its DNA binding ability. More recently, the diffusion of proteomic-based techniques, which have allowed for the identification and characterization of novel STAT3-interacting proteins able to modulate STAT3 activity via its subcellular localization, interact with upstream kinases, and recruit transcriptional machinery, has raised the possibility to target such cofactors to specifically restrain STAT3 oncogenic functions. In this article, we summarize the available data about the function of STAT3 interactors in malignant cells and discuss their role as potential therapeutic targets for cancer treatment.

• STAT3
• cancer
• cytokines
• interactors
• post-translational modifications

• trim59
• glioma
• stat3
• egfr
• tc45

• Animals
• Cell Line, Tumor
• Cell Proliferation/genetics
• Cell Transformation, Neoplastic/genetics
• ErbB Receptors/metabolism
• Female
• Glioblastoma/genetics
• Glioblastoma/pathology
• Humans
• Intracellular Signaling Peptides and Proteins
• Membrane Proteins/genetics
• Metalloproteins/genetics
• Mice
• Mice, Nude
• Neural Stem Cells/cytology
• Phosphorylation/drug effects
• Protein Tyrosine Phosphatase, Non-Receptor Type 2/metabolism
• RNA Interference
• RNA, Small Interfering/genetics
• SOX9 Transcription Factor/metabolism
• STAT3 Transcription Factor/metabolism
• Transcriptional Activation/genetics
• Tripartite Motif Proteins

• L32 MD010147 NIMHD NIH HHS
• R01 NS095634 NINDS NIH HHS
• R21 CA209345 NCI NIH HHS
• R01 CA159811 NCI NIH HHS
• R01 NS093843 NINDS NIH HHS
• T32 CA070085 NCI NIH HHS

• STAT3
• adaptor protein
• c-CBL
• prostate cancer
• protein degradation
• signal transduction

Signal transducers and activators of transcription (STATs) mediate essential signals for various biological processes, including immune responses, hematopoiesis, and neurogenesis. STAT3, for example, is involved in the pathogenesis of various human diseases, including cancers, autoimmune and inflammatory disorders. STAT3 activation is therefore tightly regulated at multiple levels to prevent these pathological conditions. A number of proteins have been reported to associate with STAT3 and regulate its activity. These STAT3-interacting proteins function to modulate STAT3-mediated signaling at various steps and mediate the crosstalk of STAT3 with other cellular signaling pathways. This article reviews the roles of novel STAT3 binding partners such as DAXX, zipper-interacting protein kinase, Krüppel-associated box-associated protein 1, Y14, PDZ and LIM domain 2 and signal transducing adaptor protein-2, in the regulation of STAT3-mediated signaling.

• Janus kinase/signal transducer and activator of transcription
• Signal transduction
• Signal transducer and activator of transcription 3
• DAXX
• Zipper-interacting protein kinase
• Krüppel-associated box-associated protein 1
• Y14
• PDZ and LIM domain 2
• Signal transducing adaptor protein-2
• Nuclear factor-κB

Protein tyrosine kinase 6 (PTK6) is a non-receptor tyrosine kinase that is highly expressed in Human Epidermal Growth Factor 2⁺ (Her2⁺) breast cancers. Overexpression of PTK6 enhances anchorage-independent survival, proliferation, and migration of breast cancer cells. We hypothesized that PTK6 inhibition is an effective strategy to inhibit growth and survival of Her2⁺ breast cancer cells, including those that are relatively resistant to Lapatinib, a targeted therapy for Her2⁺ breast cancer, either intrinsically or acquired after continuous drug exposure.

To determine the effects of PTK6 inhibition on Lapatinib-resistant Her2⁺ breast cancer cell lines (UACC893R1 and MDA-MB-453), we used short hairpin ribonucleic acid (shRNA) vectors to downregulate PTK6 expression. We determined the effects of PTK6 downregulation on growth and survival in vitro and in vivo, as well as the mechanisms responsible for these effects.

Lapatinib treatment of “sensitive” Her2⁺ cells induces apoptotic cell death and enhances transcript and protein levels of Bim, a pro-apoptotic Bcl2 family member. In contrast, treatment of relatively “resistant” Her2⁺ cells fails to induce Bim or enhance levels of cleaved, poly-ADP ribose polymerase (PARP). Downregulation of PTK6 expression in these “resistant” cells enhances Bim expression, resulting in apoptotic cell death. PTK6 downregulation impairs growth of these cells in in vitro 3-D Matrigel^TM cultures, and also inhibits growth of Her2⁺ primary tumor xenografts. Bim expression is critical for apoptosis induced by PTK6 downregulation, as co-expression of Bim shRNA rescued these cells from PTK6 shRNA-induced death. The regulation of Bim by PTK6 is not via changes in Erk/MAPK or Akt signaling, two pathways known to regulate Bim expression. Rather, PTK6 downregulation activates p38, and pharmacological inhibition of p38 activity prevents PTK6 shRNA-induced Bim expression and partially rescues cells from apoptosis.

PTK6 downregulation induces apoptosis of Lapatinib-resistant Her2⁺ breast cancer cells by enhancing Bim expression via p38 activation. As Bim expression is a critical biomarker for response to many targeted therapies, PTK6 inhibition may offer a therapeutic approach to treating patients with Her2 targeted therapy-resistant breast cancers.

The online version of this article (doi:10.1186/s13058-015-0594-z) contains supplementary material, which is available to authorized users.

• BRK
• Breast cancer
• Breast tumor kinase
• PTK6
• Src
• Tyrosine kianse

• Breast cancer
• Chemo-resistance
• Microenvironment
• Signaling pathways
• Targeted therapies

• Breast Neoplasms/drug therapy
• Breast Neoplasms/metabolism
• Breast Neoplasms/pathology
• Cell Cycle
• Female
• Hormones/metabolism
• Humans
• Molecular Targeted Therapy
• Signal Transduction
• Tumor Microenvironment

• Breast Neoplasms/genetics
• Breast Neoplasms/metabolism
• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• DNA-Binding Proteins/metabolism
• Female
• Gene Expression Regulation, Neoplastic
• Genes, Tumor Suppressor
• Green Fluorescent Proteins/chemistry
• HEK293 Cells
• Humans
• Neoplasm Proteins/metabolism
• Phosphoproteins/metabolism
• Phosphorylation
• Proteasome Endopeptidase Complex/metabolism
• Protein-Tyrosine Kinases/metabolism
• RNA-Binding Proteins/metabolism
• Signal Transduction
• src Homology Domains

Protein tyrosine kinase 6 (PTK6, also called BRK) is an intracellular tyrosine kinase expressed in the majority of human breast tumors and breast cancer cell lines, but its expression has not been reported in normal mammary gland. To study functions of PTK6 in vivo, we generated and characterized several transgenic mouse lines with expression of human PTK6 under control of the mouse mammary tumor virus (MMTV) long terminal repeat. Ectopic active PTK6 was detected in luminal epithelial cells of mature transgenic mammary glands. Lines expressing the MMTV-PTK6 transgene exhibited more than a two-fold increase in mammary gland tumor formation compared with nontransgenic control animals. PTK6 activates signal transducer and activator of transcription 3 (STAT3), and active STAT3 was detected in PTK6-positive mammary gland epithelial cells. Endogenous mouse PTK6 was not detected in the normal mouse mammary gland, but it was induced in mouse mammary gland tumors of different origin, including spontaneous tumors that developed in control mice, and tumors that formed in PTK6, H-Ras, ERBB2 and PyMT transgenic models. MMTV-PTK6 and MMTV-ERBB2 transgenic mice were crossed to explore crosstalk between PTK6 and ERBB2 signaling in vivo. We found no significant increase in tumor incidence, size or metastasis in ERBB2/PTK6 double transgenic mice. Although we detected increased proliferation in ERBB2/PTK6 double transgenic tumors, an increase in apoptosis was also observed. MMTV-PTK6 clearly promotes mammary gland tumorigenesis in vivo, but its impact may be underrepresented in our transgenic models because of induction of endogenous PTK6 expression.

CRIP1 (cysteine-rich intestinal protein 1) has been found in several tumor types, its prognostic impact and its role in cellular processes, particularly in breast cancer, are still unclear.

To elucidate the prognostic impact of CRIP1, we analyzed tissues from 113 primary invasive ductal breast carcinomas using immunohistochemistry. For the functional characterization of CRIP1, its endogenous expression was transiently downregulated in T47D and BT474 breast cancer cells and the effects analyzed by immunoblotting, WST-1 proliferation assay and invasion assay.

We found a significant correlation between CRIP1 and HER2 (human epidermal growth factor receptor 2) expression levels (p = 0.016) in tumor tissues. In Kaplan Meier analyses, CRIP1 expression was significantly associated with the distant metastases-free survival of patients, revealing a better prognosis for high CRIP1 expression (p = 0.039). Moreover, in multivariate survival analyses, the expression of CRIP1 was an independent negative prognostic factor, along with the positive prognosticators nodal status and tumor size (p = 0.029). CRIP1 knockdown in the T47D and BT474 breast cancer cell lines led to the increased phosphorylation of MAPK and Akt, to the reduced phosphorylation of cdc2, and to a significantly elevated cell proliferation in vitro (p < 0.001). These results indicate that reduced CRIP1 levels may increase cell proliferation and activate cell growth. In addition, CRIP1 knockdown increased cell invasion in vitro.

Because the lack of CRIP1 expression in breast cancer tissue is significantly associated with a worse prognosis for patients and low endogenous CRIP1 levels in vitro increased the malignant potential of breast cancer cells, we hypothesize that CRIP1 may act as a tumor suppressor in proliferation and invasion processes. Therefore, CRIP1 may be an independent prognostic marker with significant predictive power for use in breast cancer therapy.

• ptk6
• brk
• fak
• p130cas
• akt
• erk5

The aim of the study was to validate the expression of protein tyrosine kinase 6 (PTK6) in nonsmall cell lung cancer (NSCLC), and to evaluate its clinicopathological and prognostic significance.

We first conducted a meta-analysis on the mRNA profiling data sets of NSCLC in the Oncomine database. Then, one of the most significantly upregulated tyrosine kinase targets, PTK6, was further validated by immunohistochemistry in 104 primary NSCLC tumors. Furthermore the association between PTK6 expression, the clinical parameters, and overall survival was further analyzed.

Using the Oncomine database, we identified a list of tyrosine kinase genes related to NSCLC, among which PTK6 was the second most overexpressed gene (median rank = 915, P = 2.9 × 10⁻⁵). We further confirmed that NSCLC tumors had a higher expression level of PTK6 than normal pulmonary tissues. Moreover, high PTK6 expression correlated positively with shorter overall survival time, but not with other clinicopathological characteristics. In the multivariate Cox regression model, high PTK6 expression was demonstrated to be an independent prognostic factor for NSCLC patients.

Our results validated that PTK6 was found to be overexpressed in a proportion of NSCLC samples, and was associated with a poor prognosis, suggesting that this subgroup of NSCLC patients might benefit from PTK6 inhibitors in the future.

• PTK6
• nonsmall cell lung cancer
• prognosis
• target
• tyrosine kinase

• Adaptor Proteins, Signal Transducing/chemistry
• Adaptor Proteins, Signal Transducing/metabolism
• Breast/cytology
• Breast/metabolism
• Breast Neoplasms/metabolism
• Breast Neoplasms/pathology
• Cell Movement
• DNA-Binding Proteins/chemistry
• DNA-Binding Proteins/metabolism
• Disease Progression
• Female
• Hepatocyte Growth Factor/metabolism
• Humans
• Mitogen-Activated Protein Kinase 7/metabolism
• Neoplasm Proteins/metabolism
• Phosphorylation
• Protein Structure, Tertiary
• Protein-Tyrosine Kinases/metabolism
• Proto-Oncogene Proteins c-met/metabolism
• RNA-Binding Proteins/chemistry
• RNA-Binding Proteins/metabolism
• Signal Transduction
• Tyrosine/metabolism

• R01 CA107547 NCI NIH HHS
• T32 CA009138 NCI NIH HHS
• CA107547 NCI NIH HHS

• brk
• cancer cell signaling
• neoplasm
• tumor formation
• egf
• sik
• aom
• colon cancer
• stat3

• Aberrant Crypt Foci/enzymology
• Aberrant Crypt Foci/genetics
• Aberrant Crypt Foci/pathology
• Aberrant Crypt Foci/prevention & control
• Animals
• Apoptosis
• Azoxymethane
• Carcinogens
• Cell Proliferation
• Colon/enzymology
• Colon/pathology
• Colonic Neoplasms/chemically induced
• Colonic Neoplasms/enzymology
• Colonic Neoplasms/genetics
• Colonic Neoplasms/pathology
• Colonic Neoplasms/prevention & control
• Dextran Sulfate
• Disease Models, Animal
• HCT116 Cells
• Humans
• Immunoblotting
• Immunohistochemistry
• Mice
• Mice, Knockout
• Neoplasm Proteins/genetics
• Neoplasm Proteins/metabolism
• Phosphorylation
• Protein-Tyrosine Kinases/genetics
• Protein-Tyrosine Kinases/metabolism
• RNA Interference
• STAT3 Transcription Factor/genetics
• STAT3 Transcription Factor/metabolism
• Signal Transduction
• Time Factors
• src-Family Kinases/deficiency
• src-Family Kinases/genetics

• R01 DK044525 NIDDK NIH HHS
• T32 DK007739 NIDDK NIH HHS
• T32 DK07739 NIDDK NIH HHS
• DK44525 NIDDK NIH HHS

Protein tyrosine kinases (PTKs) are frequently overexpressed and/or activated in human malignancies, and regulate cancer cell proliferation, cellular survival, and migration. As such, they have become promising molecular targets for new therapies. The non-receptor PTK termed breast tumor kinase (Brk/PTK6) is overexpressed in approximately 86% of human breast tumors. The role of Brk in breast pathology is unclear.

We expressed a WAP-driven Brk/PTK6 transgene in FVB/n mice, and analyzed mammary glands from wild-type (wt) and transgenic mice after forced weaning. Western blotting and immunohistochemistry (IHC) studies were conducted to visualize markers of mammary gland involution, cell proliferation and apoptosis, as well as Brk, STAT3, and activated p38 mitogen-activated protein kinase (MAPK) in mammary tissues and tumors from WAP-Brk mice. Human (HMEC) or mouse (HC11) mammary epithelial cells were stably or transiently transfected with Brk cDNA to assay p38 MAPK signaling and cell survival in suspension or in response to chemotherapeutic agents.

Brk-transgenic dams exhibited delayed mammary gland involution and aged mice developed infrequent tumors with reduced latency relative to wt mice. Consistent with delayed involution, mammary glands of transgenic animals displayed decreased STAT3 phosphorylation, a marker of early-stage involution. Notably, p38 MAPK, a pro-survival signaling mediator downstream of Brk, was activated in mammary glands of Brk transgenic relative to wt mice. Brk-dependent signaling to p38 MAPK was recapitulated by Brk overexpression in the HC11 murine mammary epithelial cell (MEC) line and human MEC, while Brk knock-down in breast cancer cells blocked EGF-stimulated p38 signaling. Additionally, human or mouse MECs expressing Brk exhibited increased anchorage-independent survival and resistance to doxorubicin. Finally, breast tumor biopsies were subjected to IHC analysis for co-expression of Brk and phospho-p38 MAPK; ductal and lobular carcinomas expressing Brk were significantly more likely to express elevated phospho-p38 MAPK.

These studies illustrate that forced expression of Brk/PTK6 in non-transformed mammary epithelial cells mediates p38 MAPK phosphorylation and promotes increased cellular survival, delayed involution, and latent tumor formation. Brk expression in human breast tumors may contribute to progression by inducing p38-driven pro-survival signaling pathways.

• Animals
• Breast Neoplasms/drug therapy
• Breast Neoplasms/genetics
• Breast Neoplasms/metabolism
• Breast Neoplasms/pathology
• Cell Line, Tumor
• Cell Nucleus/metabolism
• Cell Nucleus/pathology
• Cell Proliferation
• Female
• Humans
• Neoplasm Proteins/genetics
• Neoplasm Proteins/metabolism
• Neoplasms/drug therapy
• Neoplasms/metabolism
• Neoplasms/pathology
• Phosphorylation
• Protein-Tyrosine Kinases/genetics
• Protein-Tyrosine Kinases/metabolism
• RNA-Binding Proteins/genetics
• RNA-Binding Proteins/metabolism
• Signal Transduction

• 1F32CA112844-01A2 NCI NIH HHS
• R01 CA107547 NCI NIH HHS
• R01 CA107547-01 NCI NIH HHS
• F32 CA112844 NCI NIH HHS
• R21 DK058347 NIDDK NIH HHS

• Animals
• Arcuate Nucleus of Hypothalamus/metabolism
• Dorsomedial Hypothalamic Nucleus/metabolism
• Gene Expression
• Gene Expression Profiling
• Glutamate Decarboxylase/genetics
• Glutamate Decarboxylase/metabolism
• Immunohistochemistry
• In Situ Hybridization
• Leptin/genetics
• Leptin/metabolism
• Mice
• Mice, Transgenic
• Microdissection
• Neurons/metabolism
• Neuropeptide Y/metabolism
• Oligonucleotide Array Sequence Analysis
• RNA, Messenger/analysis
• Receptors, Leptin/genetics
• Receptors, Leptin/metabolism
• Reverse Transcriptase Polymerase Chain Reaction

• P51 RR000163 NCRR NIH HHS
• R01 DK060685 NIDDK NIH HHS
• R01 HD014643 NICHD NIH HHS

• ptk6
• brk
• sik
• tyrosine kinase
• epithelia
• breast cancer
• colon cancer

• Animals
• Humans
• Neoplasm Proteins/chemistry
• Neoplasm Proteins/genetics
• Neoplasm Proteins/physiology
• Neoplasms/drug therapy
• Neoplasms/etiology
• Protein-Tyrosine Kinases/chemistry
• Protein-Tyrosine Kinases/genetics
• Protein-Tyrosine Kinases/physiology
• Signal Transduction

• R01 DK044525 NIDDK NIH HHS
• R01 DK068503 NIDDK NIH HHS
• DK068503 NIDDK NIH HHS
• DK44525 NIDDK NIH HHS

• Adult
• Aged
• Aged, 80 and over
• Autophagy
• Breast Neoplasms/metabolism
• Breast Neoplasms/pathology
• Carcinoma, Ductal, Breast/metabolism
• Carcinoma, Ductal, Breast/pathology
• Cell Adhesion
• Cell Proliferation
• Cell Survival
• Cells, Cultured
• Disease Progression
• Female
• Gene Expression Regulation, Enzymologic
• Gene Expression Regulation, Neoplastic
• Humans
• Middle Aged
• Neoplasm Proteins/antagonists & inhibitors
• Neoplasm Proteins/biosynthesis
• Polymerase Chain Reaction
• Protein-Tyrosine Kinases/antagonists & inhibitors
• Protein-Tyrosine Kinases/biosynthesis
• RNA Interference
• RNA, Neoplasm/analysis

• 2001:232 Breast Cancer Now
• 2002:367 Breast Cancer Now