Protein Tyrosine Kinase 6 Regulates UVB-Induced Signaling and Tumorigenesis in Mouse Skin

Abstract

Protein Tyrosine Kinase 6 (PTK6, also called BRK) is an intracellular tyrosine kinase expressed in the epithelial linings of the gastrointestinal tract and skin, where it is expressed in nondividing differentiated cells. We found PTK6 expression increases in the epidermis following UVB treatment. To evaluate the roles of PTK6 in the skin following UVB-induced damage, we exposed back skin of Ptk6 +/+ and Ptk6−/− SENCAR mice to incremental doses of UVB for thirty weeks. Wild type mice were more sensitive to UVB and exhibited increased inflammation and greater activation of STAT3 than Ptk6−/− mice. Disruption of Ptk6 did not have an impact on proliferation, although PTK6 was expressed and activated in basal epithelial cells in wild type mice following UVB treatment. However, wild type mice exhibited shortened tumor latency and increased tumor load compared with Ptk6−/− mice, and STAT3 activation was increased in these tumors. PTK6 activation was detected in UVB-induced tumors, and this correlated with increased activating phosphorylation of FAK and BCAR1. Activation of PTK6 was also detected in human squamous cell carcinomas of the skin. Although PTK6 plays roles in normal differentiation, it also contributes to UVB induced injury and tumorigenesis in vivo.

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

“…S1 A) and in most human colon tumors. In addition, manipulation of PTK6 expression did not have an impact on the activating tyrosine phosphorylation of two of its substrates, FAK (20) and BCAR1 (20) (data not shown), as previously demonstrated in human prostate cell lines (20), and in tumors that formed in mouse models of skin (16), and breast (29) cancer.…”

“…Earlier we reported that PTK6 expression levels decrease in human squamous cell carcinomas of the skin (16). Comparison of PTK6 mRNA expression in several datasets (43–50) suggests that PTK6 expression decreases in cancers that develop in tissues, which have appreciable levels of PTK6 in normal differentiated epithelial cells (Fig.…”

“…S1 A). In contrast to human prostate (5, 6), skin (16), and breast tumors (5), appreciable activation of PTK6 at the plasma membrane was not detected in colon cancer cell lines (Fig. S1 A) and in most human colon tumors.…”

“…Recently, PTK6 mRNA was identified in stromal cells of normal endometrium and breast and bladder cancers, (41). PTK6 protein expression was detected in stromal cells that had epithelial characteristics in skin spindle cell tumors (16). PTK6 expression has also been reported in activated cultured T-cells (42).…”

“…Low PTK6 expression correlates with poor prognosis in patients with laryngeal squamous cell carcinoma (14). PTK6 expression is also reduced with increasing malignancy in squamous cell carcinomas of the skin (15, 16) and oral mucosa (17). …”