The Role of Protein Tyrosine Kinase 6 in Prostate Cancer Progression

The intracellular non-receptor protein tyrosine kinase 6 (PTK6, BRK, Sik) is distantly related to SRC family kinases (SFK). PTK6 is part of family of non-receptor tyrosine kinases that also includes FRK and SRMS. Like SFK, PTK6 contains SRC homology domains required for its function; SH3, SH2 and SH1. However, PTK6 does not contain an SH4 domain needed for palmitoylation/myristylation and membrane localization although membrane localization of PTK6 is detected in breast and prostate tumors. Through intramolecular regulation, PTK6 is activated and inhibited by autophosphorylation which may be regulated by interactions with other binding partners. PTK6 promotes oncogenic signaling in breast and prostate tumors. Here, we showed that PTK6 expression is dysregulated in advanced prostate cancer. We characterized a crosstalk between PTK6, SRC and AR in prostate cancer cell lines and identified SRC and AR as new substrates of PTK6. PTK6 directly phosphorylates AR on novel tyrosine residues and induces its activity in a ligand dependent manner. PTK6 also promotes survival and growth of castration resistant prostate cancer cell lines. PTK6 phosphorylates SRC on Tyr416 and promotes its activation. Through SRC activation, PTK6 promotes activation of SHP2-ERK1/2. Inhibition of EGFR with erlotinib results in the inhibition of PTK6, AKT and ERK1/2 in control cells while no apparent change in AKT, SHP2 in cells expressing ectopic active PTK6. These studies provide insights into the complex and unique roles of PTK6 in prostate cancer by regulation of AR and SRC, and stress the importance of PTK6 as a potential therapeutic target in advanced prostate cancer.