Gene Summary

Gene:PTK6; protein tyrosine kinase 6
Aliases: BRK
Summary:The protein encoded by this gene is a cytoplasmic nonreceptor protein kinase which may function as an intracellular signal transducer in epithelial tissues. Overexpression of this gene in mammary epithelial cells leads to sensitization of the cells to epidermal growth factor and results in a partially transformed phenotype. Expression of this gene has been detected at low levels in some breast tumors but not in normal breast tissue. The encoded protein has been shown to undergo autophosphorylation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2012]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:protein-tyrosine kinase 6
Source:NCBIAccessed: 20 August, 2015


What does this gene/protein do?
Show (19)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 20 August 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Ovarian Cancer
  • Gene Expression
  • Chromosome 20
  • Cancer Gene Expression Regulation
  • HEK293 Cells
  • Phosphorylation
  • p38 Mitogen-Activated Protein Kinases
  • Cell Proliferation
  • Down-Regulation
  • rac1 GTP-Binding Protein
  • Transcription
  • Messenger RNA
  • siRNA
  • Receptor, erbB-2
  • RNA Interference
  • Gene Amplification
  • Proteolysis
  • Cell Growth Processes
  • Immunoprecipitation
  • Immunohistochemistry
  • Signal Transduction
  • Protein Binding
  • Polymerase Chain Reaction
  • Cell Nucleus
  • DNA-Binding Proteins
  • Cell Cycle
  • Receptor, EphA4
  • Cell Movement
  • Receptor Protein-Tyrosine Kinases
  • Neoplasm Proteins
  • AKT1
  • Western Blotting
  • Protein-Tyrosine Kinases
  • Breast Cancer
  • Gene Knockdown Techniques
  • Prostate Cancer
  • Thiazoles
  • RNA-Binding Proteins
  • Enzyme Activation
  • Xenograft Models
Tag cloud generated 20 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: PTK6 (cancer-related)

Tsui T, Miller WT
Cancer-Associated Mutations in Breast Tumor Kinase/PTK6 Differentially Affect Enzyme Activity and Substrate Recognition.
Biochemistry. 2015; 54(20):3173-82 [PubMed] Related Publications
Brk (breast tumor kinase, also known as PTK6) is a nonreceptor tyrosine kinase that is aberrantly expressed in several cancers and promotes cell proliferation and transformation. Genome sequencing studies have revealed a number of cancer-associated somatic mutations in the Brk gene; however, their effect on Brk activity has not been examined. We analyzed a panel of cancer-associated mutations and determined that several of the mutations activate Brk, while two eliminated enzymatic activity. Three of the mutations (L16F, R131L, and P450L) are located in important regulatory domains of Brk (the SH3, SH2 domains, and C-terminal tail, respectively). Biochemical data suggest that they activate Brk by disrupting intramolecular interactions that normally maintain Brk in an autoinhibited conformation. We also observed differential effects on recognition and phosphorylation of substrates, suggesting that the mutations can influence downstream Brk signaling by multiple mechanisms.

Ou O, Huppi K, Chakka S, et al.
Loss-of-function RNAi screens in breast cancer cells identify AURKB, PLK1, PIK3R1, MAPK12, PRKD2, and PTK6 as sensitizing targets of rapamycin activity.
Cancer Lett. 2014; 354(2):336-47 [PubMed] Article available free on PMC after 28/11/2015 Related Publications
The use of molecularly targeted drugs as single agents has shown limited utility in many tumor types, largely due to the complex and redundant nature of oncogenic signaling networks. Targeting of the PI3K/AKT/mTOR pathway through inhibition of mTOR in combination with aromatase inhibitors has seen success in particular sub-types of breast cancer and there is a need to identify additional synergistic combinations to maximize the clinical potential of mTOR inhibitors. We have used loss-of-function RNAi screens of the mTOR inhibitor rapamycin to identify sensitizers of mTOR inhibition. RNAi screens conducted in combination with rapamycin in multiple breast cancer cell lines identified six genes, AURKB, PLK1, PIK3R1, MAPK12, PRKD2, and PTK6 that when silenced, each enhanced the sensitivity of multiple breast cancer lines to rapamycin. Using selective pharmacological agents we confirmed that inhibition of AURKB or PLK1 synergizes with rapamycin. Compound-associated gene expression data suggested histone deacetylation (HDAC) inhibition as a strategy for reducing the expression of several of the rapamycin-sensitizing genes, and we tested and validated this using the HDAC inhibitor entinostat in vitro and in vivo. Our findings indicate new approaches for enhancing the efficacy of rapamycin including the use of combining its application with HDAC inhibition.

Sallam AA, Mohyeldin MM, Foudah AI, et al.
Marine natural products-inspired phenylmethylene hydantoins with potent in vitro and in vivo antitumor activities via suppression of Brk and FAK signaling.
Org Biomol Chem. 2014; 12(28):5295-303 [PubMed] Related Publications
Breast and prostate cancers are among the most common cancers worldwide with devastating statistics for the metastatic, chemotherapy- and radiotherapy-resistant phenotypes. Novel therapies interfering with new and/or multiple pathways involved in the pathology of cancer are urgently needed. Preliminary results showed that the marine natural product Z-4-hydroxyphenylmethylene hydantoin (PMH, ) and its 4-ethylthio-analog (SEth, ) promoted tight junction formation and showed anti-invasive and anti-migratory activities in vitro against metastatic prostate cancer cells and inhibited tumor growth and micrometastases in distant organs in orthotopic and transgenic mice models. This study focuses on the design and synthesis of second-generation PMHs with enhanced antitumor activities. A series of substituted benzaldehydes was selected based on earlier SAR studies and reacted with hydantoin to yield 11 new compounds . Compounds were evaluated for their antiproliferative, antimigratory and anti-invasive properties in vitro against the human mammary and prostate cancer cell lines MDA-MB-231 and PC-3, respectively. A Western blot analysis of the most active analog showed its ability to suppress the expression of the total levels of c-Met and FAK, with subsequent reduction of their phosphorylated (activated) levels in MDA-MB-231 cells. In addition, also inhibited Brk, paxillin and Rac1 phosphorylation. was formulated using hydroxypropyl β-cyclodextrin (HPCD) to improve its solubility and was further evaluated in a nude mice xenograft model using MDA-MB-231/GFP cells. PMH reduced breast tumor growth and suppressed Ki-67, CD31, p-Brk and p-FAK expression in tumor samples. Thus, is a potential lead for the control of invasive breast malignancies.

Ono H, Basson MD, Ito H
PTK6 promotes cancer migration and invasion in pancreatic cancer cells dependent on ERK signaling.
PLoS One. 2014; 9(5):e96060 [PubMed] Article available free on PMC after 28/11/2015 Related Publications
Protein Tyrosine Kinase 6 (PTK6) is a non-receptor type tyrosine kinase that may be involved in some cancers. However, the biological role and expression status of PTK6 in pancreatic cancer is unknown. Therefore in this study, we evaluated the functional role of PTK6 on pancreatic cancer invasion. Five pancreatic cancer cell lines expressed PTK6 at varying levels. PTK6 expression was also observed in human pancreatic adenocarcinomas. PTK6 suppression by siRNA significantly reduced both cellular migration and invasion (0.59/0.49 fold for BxPC3, 0.61/0.62 for Panc1, 0.42/0.39 for MIAPaCa2, respectively, p<0.05 for each). In contrast, forced overexpression of PTK6 by transfection of a PTK6 expression vector in Panc1 and MIAPaCa2 cells increased cellular migration and invasion (1.57/1.67 fold for Panc1, 1.44/1.57 for MIAPaCa2, respectively, p<0.05). Silencing PTK6 reduced ERK1/2 activation, but not AKT or STAT3 activation, while PTK6 overexpression increased ERK1/2 activation. U0126, a specific inhibitor of ERK1/2, completely abolished the effect of PTK6 overexpression on cellular migration and invasion. These results suggest that PTK6 regulates cellular migration and invasion in pancreatic cancer via ERK signaling. PTK6 may be a novel therapeutic target for pancreatic cancer.

Miah S, Goel RK, Dai C, et al.
BRK targets Dok1 for ubiquitin-mediated proteasomal degradation to promote cell proliferation and migration.
PLoS One. 2014; 9(2):e87684 [PubMed] Article available free on PMC after 28/11/2015 Related Publications
Breast tumor kinase (BRK), also known as protein tyrosine kinase 6 (PTK6), is a non-receptor tyrosine kinase overexpressed in more that 60% of human breast carcinomas. The overexpression of BRK has been shown to sensitize mammary epithelial cells to mitogenic signaling and to promote cell proliferation and tumor formation. The molecular mechanisms of BRK have been unveiled by the identification and characterization of BRK target proteins. Downstream of tyrosine kinases 1 or Dok1 is a scaffolding protein and a substrate of several tyrosine kinases. Herein we show that BRK interacts with and phosphorylates Dok1 specifically on Y362. We demonstrate that this phosphorylation by BRK significantly downregulates Dok1 in a ubiquitin-proteasome-mediated mechanism. Together, these results suggest a novel mechanism of action of BRK in the promotion of tumor formation, which involves the targeting of tumor suppressor Dok1 for degradation through the ubiquitin proteasomal pathway.

Goel RK, Miah S, Black K, et al.
The unique N-terminal region of SRMS regulates enzymatic activity and phosphorylation of its novel substrate docking protein 1.
FEBS J. 2013; 280(18):4539-59 [PubMed] Related Publications
SRMS (Src-related tyrosine kinase lacking C-terminal regulatory tyrosine and N-terminal myristoylation sites) belongs to a family of nonreceptor tyrosine kinases, which also includes breast tumour kinase and Fyn-related kinase. SRMS, similar to breast tumour kinase and Fyn-related kinase, harbours a Src homology 3 and Src homology 2, as well as a protein kinase domain. However, unlike breast tumour kinase and Fyn-related kinase, SRMS lacks a C-terminal regulatory tail but distinctively possesses an extended N-terminal region. Both breast tumour kinase and Fyn-related kinase play opposing roles in cell proliferation and signalling. SRMS, however, is an understudied member of this family. Although cloned in 1994, information on the biochemical, cellular and physiological roles of SRMS remains unreported. The present study is the first to explore the expression pattern of SRMS in breast cancers, its enzymatic activity and autoregulatory elements, and the characterization of docking protein 1 as its first bonafide substrate. We found that, similar to breast tumour kinase, SRMS is highly expressed in most breast cancers compared to normal mammary cell lines and tissues. We generated a series of SRMS point and deletion mutants and assessed enzymatic activity, subcellular localization and substrate recognition. We report for the first time that ectopically-expressed SRMS is constitutively active and that its N-terminal region regulates the enzymatic activity of the protein. Finally, we present evidence indicating that docking protein 1 is a direct substrate of SRMS. Our data demonstrate that, unlike members of the Src family, the enzymatic activity of SRMS is regulated by the intramolecular interactions involving the N-terminus of the enzyme and that docking protein 1 is a bona fide substrate of SRMS.

Fan G, Lin G, Lucito R, Tonks NK
Protein-tyrosine phosphatase 1B antagonized signaling by insulin-like growth factor-1 receptor and kinase BRK/PTK6 in ovarian cancer cells.
J Biol Chem. 2013; 288(34):24923-34 [PubMed] Article available free on PMC after 28/11/2015 Related Publications
Ovarian cancer, which is the leading cause of death from gynecological malignancies, is a heterogeneous disease known to be associated with disruption of multiple signaling pathways. Nevertheless, little is known regarding the role of protein phosphatases in the signaling events that underlie the disease; such knowledge will be essential to gain a complete understanding of the etiology of the disease and how to treat it. We have demonstrated that protein-tyrosine phosphatase 1B (PTP1B) was underexpressed in a panel of ovarian carcinoma-derived cell lines, compared with immortalized human ovarian surface epithelial cell lines. Stable restoration of PTP1B in those cancer cell lines substantially decreased cell migration and invasion, as well as proliferation and anchorage-independent survival. Mechanistically, the pro-survival IGF-1R signaling pathway was attenuated upon ectopic expression of PTP1B. This was due to dephosphorylation by PTP1B of IGF-1R β-subunit and BRK/PTK6, an SRC-like protein-tyrosine kinase that physically and functionally interacts with the IGF-1R β-subunit. Restoration of PTP1B expression led to enhanced activation of BAD, one of the major pro-death members of the BCL-2 family, which triggered cell death through apoptosis. Conversely, inhibition of PTP1B with a small molecular inhibitor, MSI-1436, increased proliferation and migration of immortalized HOSE cell lines. These data reveal an important role for PTP1B as a negative regulator of BRK and IGF-1Rβ signaling in ovarian cancer cells.

Liu LN, Huang PY, Lin ZR, et al.
Protein tyrosine kinase 6 is associated with nasopharyngeal carcinoma poor prognosis and metastasis.
J Transl Med. 2013; 11:140 [PubMed] Article available free on PMC after 28/11/2015 Related Publications
BACKGROUND: The aim of this study was to analyze the expression of protein tyrosine kinase 6 (PTK6) in nasopharyngeal carcinoma (NPC) samples, and to identify whether PTK6 can serve as a biomarker for the diagnosis and prognosis of NPC.
METHODS: We used quantitative RT-PCR and Western blotting analysis to detect mRNA and protein expression of PTK6 in NPC cell lines and immortalized nasopharyngeal epithelial cell lines. 31 NPC and 16 non-tumorous nasopharyngeal mucosa biopsies were collected to detect the difference in the expression of mRNA level of PTK6 by quantitative RT-PCR. We also collected 178 NPC and 10 normal nasopharyngeal epithelial cases with clinical follow-up data to investigate the expression of PTK6 by immunohistochemistry staining (IHC). PTK6 overexpression on cell growth and colony formation ability were measured by the method of cell proliferation assay and colony formation assay.
RESULTS: The expression of PTK6 was higher in most of NPC cell lines at both mRNA and protein levels than in immortalized nasopharyngeal epithelial cell lines (NPECs) induced by Bmi-1 (Bmi-1/NPEC1, and Bmi-1/NPEC2). The mRNA level of PTK6 was high in NPC biopsies compared to non-tumorous nasopharyngeal mucosa biopsies. IHC results showed the expression of PTK6 was significantly correlated to tumor size (P<0.001), clinical stage (P<0.001), and metastasis (P=0.016). The patients with high-expression of PTK6 had a significantly poor prognosis compared to those of low-expression (47.8% versus 80.0%, P<0.001), especially in the patients at the advanced stages (42.2% versus 79.1%, P<0.001). Multivariate analysis indicated that the level of PTK6 expression was an independent prognostic factor for the overall survival of patients with NPC (P <0.001). Overexpression of PTK6 in HNE1 cells enhanced the ability of cell proliferation and colony formation.
CONCLUSIONS: Our results suggest that high-expression of PTK6 is an independent factor for NPC patients and it might serve as a potential prognostic biomarker for patients with NPC.

Ai M, Qiu S, Lu Y, Fan Z
HER2 regulates Brk/PTK6 stability via upregulating calpastatin, an inhibitor of calpain.
Cell Signal. 2013; 25(9):1754-61 [PubMed] Article available free on PMC after 28/11/2015 Related Publications
Breast tumor kinase (Brk), also known as protein kinase-6 (PTK6), is a nonreceptor protein-tyrosine kinase that has a close functional relationship with the human epidermal growth factor receptor 2 (HER2). High levels of Brk were found in HER2-positive tumor specimens from patients with invasive ductal breast cancer; however, the underlying mechanism of the co-overexpression of Brk and HER2 remains elusive. In the current study, we explored the mechanism of HER2 and Brk co-overexpression in breast cancer cells by investigating the effect of overexpression and knockdown of HER2 on the level of Brk in breast cancer cells. We found that Brk was more stable in HER2-elevated cells than in control vector-transfected cells and was less stable in HER2 siRNA-treated cells than in control siRNA-treated cells, suggesting that HER2 regulates Brk protein stability. Further studies indicated that degradation of Brk involved a calpain-1-mediated proteolytic pathway and indicated an inverse relationship between the level of HER2 expression and calpain-1 activity. We found that HER2 inhibited calpain-1 activity through upregulating calpastatin, an endogenous calpain inhibitor. Silencing of HER2 downregulated calpastatin, and the downregulation could be rescued by overexpression of constitutively active MEK. Together, these data offer novel mechanistic insights into the functional relationship between Brk and HER2.

Ludyga N, Anastasov N, Rosemann M, et al.
Effects of simultaneous knockdown of HER2 and PTK6 on malignancy and tumor progression in human breast cancer cells.
Mol Cancer Res. 2013; 11(4):381-92 [PubMed] Related Publications
Breast cancer is the most common malignancy in women of the Western world. One prominent feature of breast cancer is the co- and overexpression of HER2 and protein tyrosine kinase 6 (PTK6). According to the current clinical cancer therapy guidelines, HER2-overexpressing tumors are routinely treated with trastuzumab, a humanized monoclonal antibody targeting HER2. Approximately, 30% of HER2-overexpressing breast tumors at least initially respond to the anti-HER2 therapy, but a subgroup of these tumors develops resistance shortly after the administration of trastuzumab. A PTK6-targeted therapy does not yet exist. Here, we show for the first time that the simultaneous knockdown in vitro, compared with the single knockdown of HER2 and PTK6, in particular in the trastuzumab-resistant JIMT-1 cells, leads to a significantly decreased phosphorylation of crucial signaling proteins: mitogen-activated protein kinase 1/3 (MAPK 1/3, ERK 1/2) and p38 MAPK, and (phosphatase and tensin homologue deleted on chromosome ten) PTEN that are involved in tumorigenesis. In addition, dual knockdown strongly reduced the migration and invasion of the JIMT-1 cells. Moreover, the downregulation of HER2 and PTK6 led to an induction of p27, and the dual knockdown significantly diminished cell proliferation in JIMT-1 and T47D cells. In vivo experiments showed significantly reduced levels of tumor growth following HER2 or PTK6 knockdown. Our results indicate a novel strategy also for the treatment of trastuzumab resistance in tumors. Thus, the inhibition of these two signaling proteins may lead to a more effective control of breast cancer.

Kang SA, Lee ST
PTK6 promotes degradation of c-Cbl through PTK6-mediated phosphorylation.
Biochem Biophys Res Commun. 2013; 431(4):734-9 [PubMed] Related Publications
PTK6 (also known as Brk) is an intracellular tyrosine kinase which induces proliferation, anti-apoptosis, migration, and anchorage-independent growth. Herein we report that PTK6 phosphorylates and down-regulates E3 ubiquitin ligase c-Cbl. Tyr(700), Tyr(731), and Tyr(774) residues in the C-terminal domain of c-Cbl are major phosphorylation sites targeted by PTK6. The phosphorylated c-Cbl is subjected to auto-ubiquitination and degraded through the ubiquitin-proteasome pathway. These results provide evidence for a novel mechanism demonstrating the oncogenic potential of PTK6 through degradation of c-Cbl, which is an E3 ligase important in down-regulation of oncoproteins.

Ai M, Liang K, Lu Y, et al.
Brk/PTK6 cooperates with HER2 and Src in regulating breast cancer cell survival and epithelial-to-mesenchymal transition.
Cancer Biol Ther. 2013; 14(3):237-45 [PubMed] Article available free on PMC after 28/11/2015 Related Publications
Breast tumor kinase (Brk)/protein tyrosine kinase-6 (PTK-6) is a nonreceptor PTK commonly expressed at high levels in breast cancer. Brk interacts closely with members of the human epidermal growth factor receptor (HER) family in breast cancer but the functional role of this interaction remains to be determined. Here, we provide novel mechanistic insights into the role of Brk in regulating cell survival and epithelial-to-mesenchymal transition (EMT) in the context of HER2-positive breast cancer cells. Overexpression of HER2 in MCF7 breast cancer cells (MCF7HER2) led to a higher level of Brk protein and concomitantly reduced Src Y416-phosphorylation, and the cells became mesenchymal in morphology. An in vivo selection of MCF7HER2 cells in nude mice resulted in a subline, termed EMT1, that exhibited not only mesenchymal morphology but also enhanced migration potential. Compared with MCF7HER2 cells, EMT1 cells maintained a similar level of HER2 protein but had much higher level of activated HER2, and the increase in Brk protein and the decrease in Src Y416-phosphorylation were less in EMT1 cells. EMT1 cells exhibited increased sensitivity to both pharmacological inhibition of HER2 and knockdown of Brk than did MCF7HER2 cells. Knockdown of Brk induced apoptosis and partially reversed the EMT phenotype in EMT1 cells. Overexpression of a constitutively active STAT3, a known substrate of Brk, overcame Brk knockdown-induced effects in EMT1 cells. Together, our findings support a new paradigm wherein Brk plays both a complementary and a counterbalancing role in cooperating with HER2 and Src to regulate breast cancer cell survival and EMT.

Zheng Y, Gierut J, Wang Z, et al.
Protein tyrosine kinase 6 protects cells from anoikis by directly phosphorylating focal adhesion kinase and activating AKT.
Oncogene. 2013; 32(36):4304-12 [PubMed] Article available free on PMC after 28/11/2015 Related Publications
Protein tyrosine kinase 6 (PTK6) is a non-receptor tyrosine kinase expressed in epithelial cancers. Disruption of Ptk6 decreases azoxymethane-induced colon tumorigenesis in mice by preventing signal transducer and activator of transcription 3 activation. Relocalization of PTK6 in prostate cancers contributes to increased growth. Although not expressed in normal breast or ovary, PTK6 promotes anchorage-independent survival of breast and ovarian tumor cells. We identified several potential PTK6 substrates in the human SW620 colon cancer cell line using mass spectrometry, including FAK (focal adhesion kinase). We show that FAK is a direct substrate of PTK6 in vitro and in vivo. Expression of membrane-targeted active PTK6 (Palm-PTK6-YF) induces constitutive activation of FAK and cell morphology changes, which are independent of SRC family kinases in Src-/-, Yes-/-, Fyn-/- (SYF) mouse embryonic fibroblasts (MEFs). Palm-PTK6-YF expressing SYF cells are transformed and overcome contact inhibition, form colonies in transformation assays, proliferate in suspension and form tumors in a xenograft model. Expression of FAK and Palm-PTK6-YF in Fak-/- MEFs synergistically activates AKT and protects cells against anoikis. However, expression of Palm-PTK6-YF in Akt1/2-/- MEFs fails to protect cells from anoikis, indicating AKT is critical in PTK6 and FAK-mediated survival signaling. In a conditional Pten knockout murine prostate cancer model, we identify prostate epithelial cells with enhanced activation of endogenous PTK6 and FAK at the plasma membrane. Knockdown of PTK6 in the PC3 human prostate cancer cell line disrupts FAK and AKT activation and promotes anoikis, which can be rescued by exogenous expression of FAK. Our data reveal important roles for a PTK6-FAK-AKT signaling axis in promoting anchorage-independent cell survival.

Gierut JJ, Mathur PS, Bie W, et al.
Targeting protein tyrosine kinase 6 enhances apoptosis of colon cancer cells following DNA damage.
Mol Cancer Ther. 2012; 11(11):2311-20 [PubMed] Article available free on PMC after 28/11/2015 Related Publications
Protein tyrosine kinase 6 (PTK6) is an intracellular tyrosine kinase that has distinct functions in normal epithelia and cancer. It is expressed primarily in nondividing epithelial cells in the normal intestine, where it promotes differentiation. However, after DNA damage, PTK6 is induced in proliferating progenitor cells, where it contributes to apoptosis. We examined links between PTK6 and the tumor suppressor p53 in the isogenic p53(+/+) and p53(-/-) HCT116 colon tumor cell lines. We found that p53 promotes expression of PTK6 in HCT116 cells, and short hairpin RNA-mediated knockdown of PTK6 leads to reduced induction of the cyclin-dependent kinase inhibitor p21. Knockdown of PTK6 enhances apoptosis in HCT116 cells with wild-type p53, following treatment of cells with γ-radiation, doxorubicin, or 5-fluorouracil. No differences in the activation of AKT, ERK1/2, or ERK5, known PTK6-regulated prosurvival signaling proteins, were detected. However, activity of STAT3, a PTK6 substrate, was impaired in cells with knockdown of PTK6 following DNA damage. In contrast to its role in the normal epithelium following DNA damage, PTK6 promotes survival of cancer cells with wild-type p53 by promoting p21 expression and STAT3 activation. Targeting PTK6 in combination with use of chemotherapeutic drugs or radiation may enhance death of colon tumor cells with wild-type p53.

Xie T, D' Ario G, Lamb JR, et al.
A comprehensive characterization of genome-wide copy number aberrations in colorectal cancer reveals novel oncogenes and patterns of alterations.
PLoS One. 2012; 7(7):e42001 [PubMed] Article available free on PMC after 28/11/2015 Related Publications
To develop a comprehensive overview of copy number aberrations (CNAs) in stage-II/III colorectal cancer (CRC), we characterized 302 tumors from the PETACC-3 clinical trial. Microsatellite-stable (MSS) samples (n = 269) had 66 minimal common CNA regions, with frequent gains on 20 q (72.5%), 7 (41.8%), 8 q (33.1%) and 13 q (51.0%) and losses on 18 (58.6%), 4 q (26%) and 21 q (21.6%). MSS tumors have significantly more CNAs than microsatellite-instable (MSI) tumors: within the MSI tumors a novel deletion of the tumor suppressor WWOX at 16 q23.1 was identified (p<0.01). Focal aberrations identified by the GISTIC method confirmed amplifications of oncogenes including EGFR, ERBB2, CCND1, MET, and MYC, and deletions of tumor suppressors including TP53, APC, and SMAD4, and gene expression was highly concordant with copy number aberration for these genes. Novel amplicons included putative oncogenes such as WNK1 and HNF4A, which also showed high concordance between copy number and expression. Survival analysis associated a specific patient segment featured by chromosome 20 q gains to an improved overall survival, which might be due to higher expression of genes such as EEF1B2 and PTK6. The CNA clustering also grouped tumors characterized by a poor prognosis BRAF-mutant-like signature derived from mRNA data from this cohort. We further revealed non-random correlation between CNAs among unlinked loci, including positive correlation between 20 q gain and 8 q gain, and 20 q gain and chromosome 18 loss, consistent with co-selection of these CNAs. These results reinforce the non-random nature of somatic CNAs in stage-II/III CRC and highlight loci and genes that may play an important role in driving the development and outcome of this disease.

Park JH, Darvin P, Lim EJ, et al.
Hwanggeumchal sorghum induces cell cycle arrest, and suppresses tumor growth and metastasis through Jak2/STAT pathways in breast cancer xenografts.
PLoS One. 2012; 7(7):e40531 [PubMed] Article available free on PMC after 28/11/2015 Related Publications
BACKGROUND: Cancer is one of the highly virulent diseases known to humankind with a high mortality rate. Breast cancer is the most common cancer in women worldwide. Sorghum is a principal cereal food in many parts of the world, and is critical in folk medicine of Asia and Africa. In the present study, we analyzed the effects of HSE in metastatic breast cancer.
METHODOLOGY/PRINCIPAL FINDINGS: Preliminary studies conducted on MDA-MB 231 and MCF-7 xenograft models showed tumor growth suppression by HSE. Western blotting studies conducted both in vivo and in vitro to check the effect of HSE in Jak/STAT pathways. Anti-metastatic effects of HSE were confirmed using both MDA-MB 231 and MCF-7 metastatic animal models. These studies showed that HSE can modulate Jak/STAT pathways, and it hindered the STAT5b/IGF-1R and STAT3/VEGF pathways not only by down-regulating the expression of these signal molecules and but also by preventing their phosphorylation. The expression of angiogenic factors like VEGF, VEGF-R2 and cell cycle regulators like cyclin D, cyclin E, and pRb were found down-regulated by HSE. In addition, it also targets Brk, p53, and HIF-1α for anti-cancer effects. HSE induced G1 phase arrest and migration inhibition in MDA-MB 231 cells. The metastasis of breast cancer to the lungs also found blocked by HSE in the metastatic animal model.
CONCLUSIONS/SIGNIFICANCE: Usage of HS as a dietary supplement is an inexpensive natural cancer therapy, without any side effects. We strongly recommend the use of HS as an edible therapeutic agent as it possesses tumor suppression, migration inhibition, and anti-metastatic effects on breast cancer.

Ma S, Bao JY, Kwan PS, et al.
Identification of PTK6, via RNA sequencing analysis, as a suppressor of esophageal squamous cell carcinoma.
Gastroenterology. 2012; 143(3):675-86.e1-12 [PubMed] Related Publications
BACKGROUND & AIMS: Esophageal squamous cell carcinoma (ESCC) is the most commonly observed histologic subtype of esophageal cancer. ESCC is believed to develop via accumulation of numerous genetic alterations, including inactivation of tumor suppressor genes and activation of oncogenes. We searched for transcripts that were altered in human ESCC samples compared with nontumor tissues.
METHODS: We performed integrative transcriptome sequencing (RNA-Seq) analysis using ESCC samples from 3 patients and adjacent nontumor tissues to identify transcripts that were altered in ESCC tissue. We performed molecular and functional studies of the transcripts identified and investigated the mechanisms of alteration.
RESULTS: We identified protein tyrosine kinase 6 (PTK6) as a transcript that was significantly down-regulated in ESCC tissues and cell lines compared with nontumor tissues or immortalized normal esophageal cell lines. The promoter of the PTK6 gene was inactivated in ESCC tissues at least in part via hypermethylation and histone deacetylation. Knockdown of PTK6 in KYSE30 ESCC cells using small hairpin RNAs increased their ability to form foci, migrate, and invade extracellular matrix in culture and form tumors in nude mice. Overexpression of PTK6 in these cells reduced their proliferation in culture and tumor formation in mice. PTK6 reduced phosphorylation of Akt and glycogen synthase kinase (GSK)3β, leading to activation of β-catenin.
CONCLUSIONS: PTK6 was identified as a transcript that is down-regulated in human ESCC tissues via epigenetic modification at the PTK6 locus. Its product appears to regulate cell proliferation by reducing phosphorylation of Akt and GSK3β, leading to activation of β-catenin. Reduced levels of PTK6 promote growth of xenograft tumors in mice; it might be developed as a marker of ESCC.

Lim EJ, Hong DY, Park JH, et al.
Methylsulfonylmethane suppresses breast cancer growth by down-regulating STAT3 and STAT5b pathways.
PLoS One. 2012; 7(4):e33361 [PubMed] Article available free on PMC after 28/11/2015 Related Publications
Breast cancer is the most aggressive form of all cancers, with high incidence and mortality rates. The purpose of the present study was to investigate the molecular mechanism by which methylsulfonylmethane (MSM) inhibits breast cancer growth in mice xenografts. MSM is an organic sulfur-containing natural compound without any toxicity. In this study, we demonstrated that MSM substantially decreased the viability of human breast cancer cells in a dose-dependent manner. MSM also suppressed the phosphorylation of STAT3, STAT5b, expression of IGF-1R, HIF-1α, VEGF, BrK, and p-IGF-1R and inhibited triple-negative receptor expression in receptor-positive cell lines. Moreover, MSM decreased the DNA-binding activities of STAT5b and STAT3, to the target gene promoters in MDA-MB 231 or co-transfected COS-7 cells. We confirmed that MSM significantly decreased the relative luciferase activities indicating crosstalk between STAT5b/IGF-1R, STAT5b/HSP90α, and STAT3/VEGF. To confirm these findings in vivo, xenografts were established in Balb/c athymic nude mice with MDA-MB 231 cells and MSM was administered for 30 days. Concurring to our in vitro analysis, these xenografts showed decreased expression of STAT3, STAT5b, IGF-1R and VEGF. Through in vitro and in vivo analysis, we confirmed that MSM can effectively regulate multiple targets including STAT3/VEGF and STAT5b/IGF-1R. These are the major molecules involved in tumor development, progression, and metastasis. Thus, we strongly recommend the use of MSM as a trial drug for treating all types of breast cancers including triple-negative cancers.

Mahajan K, Mahajan NP
PI3K-independent AKT activation in cancers: a treasure trove for novel therapeutics.
J Cell Physiol. 2012; 227(9):3178-84 [PubMed] Article available free on PMC after 28/11/2015 Related Publications
AKT/PKB serine threonine kinase, a critical signaling molecule promoting cell growth and survival pathways, is frequently dysregulated in many cancers. Although phosphatidylinositol-3-OH kinase (PI3K), a lipid kinase, is well characterized as a major regulator of AKT activation in response to a variety of ligands, recent studies highlight a diverse group of tyrosine (Ack1/TNK2, Src, PTK6) and serine/threonine (TBK1, IKBKE, DNAPKcs) kinases that activate AKT directly to promote its pro-proliferative signaling functions. While some of these alternate AKT activating kinases respond to growth factors, others respond to inflammatory and genotoxic stimuli. A common theme emerging from these studies is that aberrant or hyperactivation of these alternate kinases is often associated with malignancy. Consequently, evaluating the use of small molecular inhibitors against these alternate AKT activating kinases at earlier stages of cancer therapy may overcome the pressing problem of drug resistance surfacing especially in patients treated with PI3K inhibitors.

Li X, Lu Y, Liang K, et al.
Brk/PTK6 sustains activated EGFR signaling through inhibiting EGFR degradation and transactivating EGFR.
Oncogene. 2012; 31(40):4372-83 [PubMed] Article available free on PMC after 28/11/2015 Related Publications
Epidermal growth factor receptor (EGFR)-mediated cell signaling is critical for mammary epithelial cell growth and survival; however, targeting EGFR has shown no or only minimal therapeutic benefit in patients with breast cancer. Here, we report a novel regulatory mechanism of EGFR signaling that may explain the low response rates. We found that breast tumor kinase (Brk)/protein-tyrosine kinase 6 (PTK6), a nonreceptor protein-tyrosine kinase highly expressed in most human breast tumors, interacted with EGFR and sustained ligand-induced EGFR signaling. We demonstrate that Brk inhibits ligand-induced EGFR degradation through uncoupling activated EGFR from casitas B-lineage lymphoma-mediated EGFR ubiquitination. In addition, upon activation by EGFR, Brk directly phosphorylated Y845 in the EGFR kinase domain, thereby further potentiating EGFR kinase activity. Experimental elevation of Brk conferred resistance of breast cancer cells to cetuximab (an EGFR-blocking antibody)-induced inhibition of cell signaling and proliferation, whereas knockdown of Brk sensitized the cells to cetuximab by inducing apoptosis. Our findings reveal a previously unknown role of Brk in EGFR-targeted therapy.

Lofgren KA, Ostrander JH, Housa D, et al.
Mammary gland specific expression of Brk/PTK6 promotes delayed involution and tumor formation associated with activation of p38 MAPK.
Breast Cancer Res. 2011; 13(5):R89 [PubMed] Article available free on PMC after 28/11/2015 Related Publications
INTRODUCTION: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.

Zeng H, Belanger DB, Curran PJ, et al.
Discovery of novel imidazo[1,2-a]pyrazin-8-amines as Brk/PTK6 inhibitors.
Bioorg Med Chem Lett. 2011; 21(19):5870-5 [PubMed] Related Publications
A series of substituted imidazo[1,2-a]pyrazin-8-amines were discovered as novel breast tumor kinase (Brk)/protein tyrosine kinase 6 (PTK6) inhibitors. Tool compounds with low-nanomolar Brk inhibition activity, high selectivity towards other kinases and desirable DMPK properties were achieved to enable the exploration of Brk as an oncology target.

Gierut J, Zheng Y, Bie W, et al.
Disruption of the mouse protein tyrosine kinase 6 gene prevents STAT3 activation and confers resistance to azoxymethane.
Gastroenterology. 2011; 141(4):1371-80, 1380.e1-2 [PubMed] Article available free on PMC after 28/11/2015 Related Publications
BACKGROUND & AIMS: Protein tyrosine kinase 6 (PTK6) is expressed throughout the gastrointestinal tract and is a negative regulator of proliferation that promotes differentiation and DNA-damage-induced apoptosis in the small intestine. PTK6 is not expressed in normal mammary gland, but is induced in most human breast tumors. Signal transducer and activator of transcription 3 (STAT3) mediates pathogenesis of colon cancer and is a substrate of PTK6. We investigated the role of PTK6 in colon tumorigenesis.
METHODS: Ptk6+/+ and Ptk6-/- mice were injected with azoxymethane alone or in combination with dextran sodium sulfate; formation of aberrant crypt foci and colon tumors was examined. Effects of disruption of Ptk6 on proliferation, apoptosis, and STAT3 activation were examined by immunoblot and immunohistochemical analyses. Regulation of STAT3 activation was examined in the HCT116 colon cancer cell line and young adult mouse colon cells.
RESULTS: Ptk6-/- mice developed fewer azoxymethane-induced aberrant crypt foci and tumors. Induction of PTK6 increased apoptosis, proliferation, and STAT3 activation in Ptk6+/+ mice injected with azoxymethane. Disruption of Ptk6 impaired STAT3 activation following azoxymethane injection, and reduced active STAT3 levels in Ptk6-/- tumors. Stable knockdown of PTK6 reduced basal levels of active STAT3, as well as activation of STAT3 by epidermal growth factor in HCT116 cells. Disruption of Ptk6 reduced activity of STAT3 in young adult mouse colon cells.
CONCLUSIONS: PTK6 promotes STAT3 activation in the colon following injection of the carcinogen azoxymethane and regulates STAT3 activity in mouse colon tumors and in the HCT116 and young adult mouse colon cell lines. Disruption of Ptk6 decreases azoxymethane-induced colon tumorigenesis in mice.

Brauer PM, Zheng Y, Evans MD, et al.
The alternative splice variant of protein tyrosine kinase 6 negatively regulates growth and enhances PTK6-mediated inhibition of β-catenin.
PLoS One. 2011; 6(3):e14789 [PubMed] Article available free on PMC after 28/11/2015 Related Publications
Protein tyrosine kinase 6 (PTK6), also called breast tumor kinase (BRK), is expressed in epithelial cells of various tissues including the prostate. Previously it was shown that PTK6 is localized to epithelial cell nuclei in normal prostate, but becomes cytoplasmic in human prostate tumors. PTK6 is also primarily cytoplasmic in the PC3 prostate adenocarcinoma cell line. Sequencing revealed expression of wild type full-length PTK6 transcripts in addition to an alternative transcript lacking exon 2 in PC3 cells. The alternative transcript encodes a 134 amino acid protein, referred to here as ALT-PTK6, which shares the first 77 amino acid residues including the SH3 domain with full length PTK6. RT-PCR was used to show that ALT-PTK6 is coexpressed with full length PTK6 in established human prostate and colon cell lines, as well as in primary cell lines derived from human prostate tissue and tumors. Although interaction between full-length PTK6 and ALT-PTK6 was not detected, ALT-PTK6 associates with the known PTK6 substrates Sam68 and β-catenin in GST pull-down assays. Coexpression of PTK6 and ALT-PTK6 led to suppression of PTK6 activity and reduced association of PTK6 with tyrosine phosphorylated proteins. While ALT-PTK6 alone did not influence β-catenin/TCF transcriptional activity in a luciferase reporter assay, it enhanced PTK6-mediated inhibition of β-catenin/TCF transcription by promoting PTK6 nuclear functions. Ectopic expression of ALT-PTK6 led to reduced expression of the β-catenin/TCF targets Cyclin D1 and c-Myc in PC3 cells. Expression of tetracycline-inducible ALT-PTK6 blocked the proliferation and colony formation of PC3 cells. Our findings suggest that ALT-PTK6 is able to negatively regulate growth and modulate PTK6 activity, protein-protein associations and/or subcellular localization. Fully understanding functions of ALT-PTK6 and its impact on PTK6 signaling will be critical for development of therapeutic strategies that target PTK6 in cancer.

Ikeda O, Mizushima A, Sekine Y, et al.
Involvement of STAP-2 in Brk-mediated phosphorylation and activation of STAT5 in breast cancer cells.
Cancer Sci. 2011; 102(4):756-61 [PubMed] Related Publications
Signal-transducing adaptor protein (STAP)-2 is a recently identified adaptor protein that contains Pleckstrin homology and Src homology 2-like domains, and is also known to be a substrate of breast tumor kinase (Brk). In a previous study, we found that STAP-2 upregulated Brk-mediated activation of signal transducer and activator of transcription (STAT) 3 in breast cancer cells. Here, we examined the involvement of STAP-2 in Brk-mediated STAT5 activation in breast cancer cells. Ectopic expression of STAP-2 induced Brk-mediated transcriptional activity of STAT5. Furthermore, STAP-2-knockdown in T47D breast cancer cells induced a marked decrease in proliferation that was as strong as that after Brk- or STAT5b-knockdown. Regarding the mechanism, the Pleckstrin homology domain of STAP-2 is likely to participate in the process by which Brk phosphorylates and activates STAT5. Taken together, our findings provide insights toward the development of novel therapeutic strategies as well as novel prognostic values in breast carcinomas.

Brauer PM, Zheng Y, Wang L, Tyner AL
Cytoplasmic retention of protein tyrosine kinase 6 promotes growth of prostate tumor cells.
Cell Cycle. 2010; 9(20):4190-9 [PubMed] Article available free on PMC after 28/11/2015 Related Publications
Protein tyrosine kinase 6 (PTK6) is an intracellular tyrosine kinase that is nuclear in epithelial cells of the normal prostate, but cytoplasmic in prostate tumors and in the PC3 prostate tumor cell line. The impact of altered PTK6 intracellular localization in prostate tumor cells has not been extensively explored. Knockdown of endogenous cytoplasmic PTK6 resulted in decreased PC3 cell proliferation and colony formation, suggesting that cytoplasmic PTK6 stimulates oncogenic pathways. In contrast, reintroduction of PTK6 into nuclei of PC3 cells had a negative effect on growth. Enhanced tyrosine phosphorylation of the PTK6 substrate Sam68 was detected in cells expressing nuclear-targeted PTK6. We found that mechanisms regulating nuclear localization of PTK6 are intact in PC3 cells. Transiently overexpressed PTK6 readily enters the nucleus. Ectopic expression of ALT-PTK6, a catalytically inactive splice variant of PTK6, did not affect localization of endogenous PTK6 in PC3 cells. Using leptomycin B, we confirmed that cytoplasmic localization of endogenous PTK6 is not due to Crm-1/exportin-1 mediated nuclear export. In addition, overexpression of the PTK6 nuclear substrate Sam68 is not sufficient to bring PTK6 into the nucleus. While exogenous PTK6 was readily detected in the nucleus when transiently expressed at high levels, low-level expression of inducible wild type PTK6 in stable cell lines resulted in its cytoplasmic retention. Our results suggest that retention of PTK6 in the cytoplasm of prostate cancer cells disrupts its ability to regulate nuclear substrates and leads to aberrant growth. In prostate cancer, restoring PTK6 nuclear localization may have therapeutic advantages.

Ikeda O, Sekine Y, Mizushima A, et al.
Interactions of STAP-2 with Brk and STAT3 participate in cell growth of human breast cancer cells.
J Biol Chem. 2010; 285(49):38093-103 [PubMed] Article available free on PMC after 28/11/2015 Related Publications
STAP-2 (signal transducing adaptor protein-2) is a recently identified adaptor protein that contains pleckstrin homology (PH) and Src homology 2-like domains, as well as a STAT3-binding motif in its C-terminal region. STAP-2 is also a substrate of breast tumor kinase (Brk). In breast cancers, Brk expression is deregulated and promotes STAT3-dependent cell proliferation. In the present study, manipulated STAP-2 expression demonstrated essential roles of STAP-2 in Brk-mediated STAT3 activation. STAP-2 interacts with both Brk and STAT3. In addition, small interfering RNA-mediated reduction of endogenous STAP-2 expression strongly decreased Brk-mediated STAT3 activation in T47D breast cancer cells. The PH domain of STAP-2 is involved in multiple steps: the binding between Brk and STAP-2, the activation and tyrosine phosphorylation of STAT3, and the activation of Brk. Notably, a STAP-2 PH-Brk fusion protein exhibited robust kinase activity and increased activation and tyrosine phosphorylation of STAT3. Finally, STAP-2 knockdown in T47D cells induced a significant decrease of proliferation, as strong as that of Brk or STAT3 knockdown. Taken together, our findings are likely to inform the development of a novel therapeutic strategy, as well as the determination of novel prognostic values, in breast carcinomas.

Ostrander JH, Daniel AR, Lange CA
Brk/PTK6 signaling in normal and cancer cell models.
Curr Opin Pharmacol. 2010; 10(6):662-9 [PubMed] Article available free on PMC after 28/11/2015 Related Publications
Breast tumor kinase (Brk), also termed PTK6, is known to function in cell-type and context-dependent processes governing normal differentiation. However, in tumors in which Brk is overexpressed, this unusual soluble tyrosine kinase is emerging as a mediator of cancer cell phenotypes, including increased proliferation, survival, and migration. Nuclear and cytoplasmic substrates phosphorylated by Brk include a collection of regulatory RNA-binding proteins, adaptor molecules that link Brk to signaling pathways generally associated with the activation of growth factor receptors, and Signal Transducers and Activators of Transcription (STAT) molecules that are direct regulators of gene expression. Understanding Brk-dependent regulation of these key signaling pathways and how they influence cancer cell behavior is predicted to inform the development of improved 'targeted' cancer therapies and may provide insight into ways to avoid chemo-resistance to established treatments.

Castro NE, Lange CA
Breast tumor kinase and extracellular signal-regulated kinase 5 mediate Met receptor signaling to cell migration in breast cancer cells.
Breast Cancer Res. 2010; 12(4):R60 [PubMed] Article available free on PMC after 28/11/2015 Related Publications
INTRODUCTION: Breast tumor kinase (Brk/protein tyrosine kinase 6 (PTK6)) is a nonreceptor, soluble tyrosine kinase overexpressed in the majority of breast tumors. Previous work has placed Brk downstream of epidermal growth factor receptor (ErbB) activation and upstream of extracellular signal-regulated kinase 5 (ERK5) and p38 mitogen-activated protein (MAP) kinases. Herein we investigate the regulation of Brk kinase activity and cell migration in response to treatment of keratinocytes (HaCaT cells) and breast cancer cell lines (MDA-MB-231 and T47D cells) with hepatocyte growth factor (HGF) and macrophage stimulating protein (MSP), peptide ligands for Met and Ron receptors, respectively.
METHODS: In vitro kinase assays were performed to directly measure Brk kinase activity in response to MET and RON ligands. Transfection of Brk-targeted RNAi was used to knock down endogenous Brk or ERK5 in multiple cell lines. Kinase activities (downstream of MET signaling) were assayed by Western blotting using total and phospho-specific antibodies. Boyden chamber assays were used to measure cell migration in response to manipulation of Brk and downstream MET effectors. Rescue experiments were performed by knock down of endogenous Brk using RNAi (targeting the untranslated region (3'-UTR)) and transient transfection (re-expression) of either wild-type or kinase-inactive Brk.
RESULTS: Brk gene silencing revealed that HGF, but not MSP, induced robust Brk-dependent cell migration. Brk and ERK5 copurified in HGF-induced protein complexes, and Brk/ERK5 complexes formed independently of Brk kinase activity. ERK5 was required for breast cancer cell but not keratinocyte cell migration, which became ERK1/2-dependent upon ERK5 knockdown. Notably, rescue experiments indicated that the kinase activity of Brk was not required for HGF-induced cell migration. Further, expression of either wild-type or kinase-inactive Brk in Brk-null MDA-MB-435 cells activated ERK5 and conferred increased HGF-induced cell migration.
CONCLUSIONS: These results have identified Brk and ERK5 as important downstream effectors of Met signaling to cell migration. Targeting ERK5 kinase activity or inhibiting the formation of Brk/ERK5 complexes may provide an additional means of blocking cell migration associated with breast cancer progression to metastasis.

Brauer PM, Tyner AL
Building a better understanding of the intracellular tyrosine kinase PTK6 - BRK by BRK.
Biochim Biophys Acta. 2010; 1806(1):66-73 [PubMed] Article available free on PMC after 28/11/2015 Related Publications
Protein tyrosine kinase 6 (PTK6), also referred to as breast tumor kinase BRK, is a member of a distinct family of kinases that is evolutionarily related to the SRC family of tyrosine kinases. While not expressed in the normal mammary gland, PTK6 expression is detected in a large proportion of human mammary gland tumors. In breast tumor cells, PTK6 promotes growth factor signaling and cell migration. PTK6 expression is also increased in a number of other epithelial tumors, including ovarian and colon cancer. In contrast, PTK6 is expressed in diverse normal epithelia, including the linings of the gastrointestinal tract, skin and prostate, where its expression correlates with cell cycle exit and differentiation. Disruption of the mouse Ptk6 gene leads to increased growth and impaired differentiation in the small intestine that is accompanied by increased AKT and Wnt signaling. Following total body irradiation, PTK6 expression is induced in proliferating progenitor cells of the intestine, where it plays an essential role in DNA-damage induced apoptosis. A distinguishing feature of PTK6 is its flexibility in intracellular localization, due to a lack of amino-terminal myristoylation/palmitoylation. Recently a number of substrates of PTK6 have been identified, including nuclear RNA-binding proteins and transcription factors. We discuss PTK6 signaling, its apparent conflicting roles in cancer and normal epithelia, and its potential as a therapeutic target in epithelial cancers.

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