Protein Tyrosine Kinase 6 Promotes Oncogenic Signaling at Cell Plasma Membrane in Prostate Cancer

Protein tyrosine kinase 6 (PTK6) is an intracellular Src-related tyrosine kinase that is localized to different cellular compartments due to the lack of an N-terminal myristoylation consensus sequence. In normal tissue, PTK6 is expressed in differentiated epithelial cells, and involved in promoting differentiation and mediating apoptosis in response to apoptotic stimuli. Elevated expression of PTK6 is detected in different types of human cancer including breast, colon, head and neck, melanoma and ovarian cancer, where it promotes cancer cell proliferation, migration and survival through different signaling pathways. In prostate cancer, we discovered elevated expression, aberrant localization and activation of PTK6. High levels of PTK6 predict low survival and high recurrence for human prostate cancer patients. As human prostate cancer progresses to advanced stages, PTK6 is translocated from nucleus to cytoplasm. This is also observed in a murine prostate cancer model. Activation of PTK6 is detected in both human and mouse prostate tumor samples. Interestingly, the pool of active PTK6, which is phosphorylated at tyrosine residue 342, is primarily associated with the cell plasma membrane. To investigate the role of PTK6 in prostate cancer, I identified several novel PTK6 substrates. I showed that PTK6 directly phosphorylates AKT, focal adhesion kinase (FAK) and p130 Crk-associated substrate (p130CAS) independent of Src family kinases. PTK6 positively regulates AKT activity by phosphorylating AKT at tyrosine residues 315 and 326. PTK6 also plays a critical role in promoting cell survival against anoikis by phosphorylating FAK and activating AKT survival signaling. In addition, PTK6 phosphorylates p130CAS and activates Erk5 to promote peripheral adhesion complex formation and cell migration. PTK6 is also involved in promoting epithelial-mesenchymal transition (EMT) of prostate cancer cells. In sum, I demonstrated that PTK6 promotes proliferation, migration, anoikis resistance, EMT, and invasion of prostate cancer cells through activating its substrates AKT, FAK and p130CAS. This study suggested that elevated PTK6 expression, translocation of PTK6 from nucleus to cytoplasm, and activation of PTK6 at plasma membrane in human prostate cancer might all contribute to the access and phosphorylation of these substrates and activation of their signaling pathways, therefore promoting prostate cancer progression.