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Context-specific protein tyrosine kinase 6 (PTK6) signalling in prostate cancer.

ABSTRACT: Protein tyrosine kinase 6 (PTK6) is an intracellular tyrosine kinase that is distantly related to SRC family kinases. PTK6 is nuclear in normal prostate epithelia, but nuclear localization is lost in prostate tumours. Increased expression of PTK6 is detected in human prostate cancer, especially at metastatic stages, and in other types of cancers, including breast, colon, head and neck cancers, and serous carcinoma of the ovary.Potential novel substrates of PTK6 identified by mass spectrometry were validated in vitro. The significance of PTK6-induced phosphorylation of these substrates was addressed using human prostate cell lines by knockdown of endogenous PTK6 or overexpression of targeted PTK6 to different intracellular compartments.We identified AKT, p130CAS and focal adhesion kinase (FAK) as novel PTK6 substrates and demonstrated their roles in promoting cell proliferation, migration and resistance to anoikis. In prostate cancer cells, active PTK6 is primarily associated with membrane compartments, although the majority of total PTK6 is localized within the cytoplasm. Ectopic expression of membrane-targeted PTK6 transforms immortalized fibroblasts. Knockdown of endogenous cytoplasmic PTK6 in PC3 prostate cancer cells impairs proliferation, migration and anoikis resistance. However, re-introduction of PTK6 into the nucleus significantly decreases cell proliferation, suggesting context-specific functions for nuclear PTK6.In human prostate cancer, elevated PTK6 expression, translocation of PTK6 from the nucleus to the cytoplasm and its activation at the plasma membrane contribute to increased phosphorylation and activation of its substrates such as AKT, p130CAS and FAK, thereby promoting prostate cancer progression.

SUBMITTER: Zheng Y

PROVIDER: S-EPMC3602132 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Context-specific protein tyrosine kinase 6 (PTK6) signalling in prostate cancer.

Zheng Yu Y Tyner Angela L AL

European journal of clinical investigation 20130210 4

<h4>Background</h4>Protein tyrosine kinase 6 (PTK6) is an intracellular tyrosine kinase that is distantly related to SRC family kinases. PTK6 is nuclear in normal prostate epithelia, but nuclear localization is lost in prostate tumours. Increased expression of PTK6 is detected in human prostate cancer, especially at metastatic stages, and in other types of cancers, including breast, colon, head and neck cancers, and serous carcinoma of the ovary.<h4>Materials and methods</h4>Potential novel subs ...[more]

PMID: 23398121

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Project description: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.

Dataset Information

Context-specific protein tyrosine kinase 6 (PTK6) signalling in prostate cancer.

Publications

Context-specific protein tyrosine kinase 6 (PTK6) signalling in prostate cancer.

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