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.