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Title:
Protein tyrosine kinase 6 protects cells from anoikis by directly phosphorylating focal adhesion kinase and activating AKT | Oncogene
Description:
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 S rc−/−, Y es−/−, F yn−/− (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.
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nature portfolio permissions reprints privacy policy nature advertising ptk6-fak-akt signaling axis author information authors social media fak-mediated survival signaling akt/pkb signaling pathway differentiation state-specific uncoupling author correspondence high-grade serous carcinoma pkb/akt phosphorylates p27 receptor tyrosine kinase oncogene e-pub ahead ferm-enhanced p53 degradation membrane-targeted active ptk6 adhesion-dependent cell survival brk tyrosine kinase anchorage-independent apoptosis springerlink instant access chan-hui py permissions focal adhesion kinase personal data tumour progression cassandra akt/pkb signaling prostate cancer metastasis prostate cancer darren prostate tumor cells brk/sik expression anchorage-independent growth human breast tumours human breast carcinomas breast cancer cells cancer cell survival breast tumor kinase phosphatidylinositol 3-kinase/akt palm-ptk6-yf data protection fak/src signaling promotes akt activation tyrosine kinases overexpressed protein kinase brk activates rac1 regulates pcna binding targeting anoikis resistance overcome contact inhibition impairs nuclear import
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headline:Protein tyrosine kinase 6 protects cells from anoikis by directly phosphorylating focal adhesion kinase and activating AKT
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Cancer
Cell signalling
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Sik
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