Context‐specific protein tyrosine kinase 6 (PTK6) signalling in prostate cancer

Abstract

Background 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 tumors. 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 ovary. Materials and Methods 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. Results We identified AKT, p130CAS and 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, reintroduction of PTK6 into the nucleus significantly decreases cell proliferation, suggesting context specific functions for nuclear PTK6. Conclusions 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.

Kinase-Dependent and -Independent Roles for PTK6 in Colon Cancer

“…Membrane-association of active PTK6 promotes tumorigenesis and the EMT in prostate cancer cells (6)(reviewed in (7)). Activation of PTK6 at the plasma membrane has also been detected in human breast tumors of different subtypes (5).…”

“…It is induced and activated in a majority of human breast tumors, where it promotes oncogenic signaling and breast tumor growth (5). In prostate cancers, PTK6 is activated and associated with the plasma membrane, where it promotes tumorigenesis and the epithelial to mesenchymal transition (EMT) (6) [reviewed in (7)]. The PTK6 gene is amplified and PTK6 is overexpressed in high-grade serous ovarian carcinomas and may promote the development and growth of ovarian tumors (8).…”

Tracing the footprints of the breast cancer oncogene BRK — Past till present

“…The association of insulin-like growth factor receptor 1R (IGF-1R) 356 with BRK is also significant since the former is expressed in many breast with previous reports [75]. Another report identified the proto-429 oncogenic protein c-cbl (cellular Casitas B-lymphoma) as a BRK sub-430 strate [76].…”

Understanding the cellular roles of Fyn-related kinase (FRK): implications in cancer biology

“…In line with these observations, it may be important to note that the functions of BRK also seem to diverge in a tissue-specific context. For instance, while BRK operates with a pro-oncogenic status in breast [86] and prostate cancer [87,88], evidence of an antagonistic role of BRK has been described in colonic tissues [89] and oesophageal cancers [90,91]. Since FRK displays divergent and sometimes opposing roles depending on the tissue or cellular context, the therapeutic benefit of targeting FRK in any malignancy will have to be tailored.…”