Oncogenic and Tumor Suppressor Roles for Protein Tyrosine Kinase 6 in Colorectal Cancer
Mathur, Priya S.
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Protein Tyrosine Kinase 6 (PTK6, also BRK) is a non-receptor tyrosine kinase expressed in differentiated epithelia of the skin, gastrointestinal tract, mammary gland and prostate. Disruption of the Ptk6 gene led to impaired intestinal differentiation and increased intestinal proliferation in mice. However, PTK6 also has a tumor-promoting role in the colon, as disruption of the Ptk6 gene impaired STAT3 activation and carcinogen-induced colon tumorigenesis in mice. These studies serve to characterize these two seemingly contradictory roles for PTK6 in the colon. PTK6 is highly expressed in epithelial-like SW480 cells and significantly reduced in mesenchymal-like SW620 cells; PTK6 activity is not detectable in either cell line. Knockdown of PTK6 in SW480 cells results in epithelial-to-mesenchymal transition (EMT); decreased E-cadherin expression and increased ZEB-1 and Vimentin; as well as increased proliferation, migration, wound-healing, anchorage-independent growth of cells in culture, and increased in vivo tumorigenesis of xenograft cells in nude mice. Ectopic expression of PTK6 in SW620 cells rescues the EMT phenotype in a kinase-independent manner. Analysis of patient tissues find high PTK6 expression in differentiated colon epithelium and downregulation of mRNA and protein levels in tumors; PTK6 protein expression inversely correlates with increasing tumor invasiveness from hyperplasia, to adenoma to invasive carcinoma. Membrane-associated active PTK6 is expressed in pockets of invasive carcinoma samples, which is not detectable in normal tissue. Serum stimulation of SW620 promotes kinase activation of overexpressed PTK6-WT and –YF, and in the PTK6-YF cells only, promotes activation of cytoplasmic oncogenic targets and downstream effectors, STAT3 and ERK5. PTK6 also promotes survival signaling following DNA damage in SW480 and HCT116 colon cancer cells; knockdown of PTK6 in these cells promotes DNA damage-induced apoptosis while cells expressing PTK6 have a survival advantage. PTK6 also promotes the activation of AKT, STAT3, and ERK1/2 in response to DNA damage. The kinase inhibitor Vemurafenib has been demonstrated to inhibit PTK6 activity with high specificity, treating SW620 PTK6-WT and -YF cells attenuates activating phosphorylation. These studies indicate that PTK6 promotes the epithelial phenotype to antagonize the EMT in a kinase-independent manner and a kinase switch activates PTK6 to promote oncogenic signaling.
tyrosine kinase, colon cancer, EMT