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Protein tyrosine kinase 6 protects cells from anoikis by directly phosphorylating focal adhesion kinase and activating AKT.
Oncogene. 2013 Sep 05; 32(36):4304-12.O

Abstract

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.

Authors+Show Affiliations

Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, College of Medicine, Chicago, IL 60607, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

23027128

Citation

Zheng, Y, et al. "Protein Tyrosine Kinase 6 Protects Cells From Anoikis By Directly Phosphorylating Focal Adhesion Kinase and Activating AKT." Oncogene, vol. 32, no. 36, 2013, pp. 4304-12.
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.
Zheng, Y., Gierut, J., Wang, Z., Miao, J., Asara, J. M., & Tyner, A. L. (2013). Protein tyrosine kinase 6 protects cells from anoikis by directly phosphorylating focal adhesion kinase and activating AKT. Oncogene, 32(36), 4304-12. https://doi.org/10.1038/onc.2012.427
Zheng Y, et al. Protein Tyrosine Kinase 6 Protects Cells From Anoikis By Directly Phosphorylating Focal Adhesion Kinase and Activating AKT. Oncogene. 2013 Sep 5;32(36):4304-12. PubMed PMID: 23027128.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Protein tyrosine kinase 6 protects cells from anoikis by directly phosphorylating focal adhesion kinase and activating AKT. AU - Zheng,Y, AU - Gierut,J, AU - Wang,Z, AU - Miao,J, AU - Asara,J M, AU - Tyner,A L, Y1 - 2012/10/01/ PY - 2012/04/25/received PY - 2012/07/24/revised PY - 2012/08/04/accepted PY - 2012/10/3/entrez PY - 2012/10/3/pubmed PY - 2013/11/2/medline SP - 4304 EP - 12 JF - Oncogene JO - Oncogene VL - 32 IS - 36 N2 - 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. SN - 1476-5594 UR - https://www.unboundmedicine.com/medline/citation/23027128/Protein_tyrosine_kinase_6_protects_cells_from_anoikis_by_directly_phosphorylating_focal_adhesion_kinase_and_activating_AKT_ L2 - http://dx.doi.org/10.1038/onc.2012.427 DB - PRIME DP - Unbound Medicine ER -