PTK6 Activation at the Membrane Regulates Epithelial–Mesenchymal Transition in Prostate Cancer

Abstract

The intracellular tyrosine kinase PTK6 lacks a membrane-targeting SH4 domain and localizes to the nuclei of normal prostate epithelial cells. However, PTK6 translocates from the nucleus to the cytoplasm in human prostate tumor cells. Here we show that while PTK6 is located primarily within the cytoplasm, the pool of active PTK6 in prostate cancer cells localizes to membranes. Ectopic expression of membrane-targeted active PTK6 promoted epithelial-mesenchymal transition in part by enhancing activation of AKT, thereby stimulating cancer cell migration and metastases in xenograft models of prostate cancer. Conversely, siRNA-mediated silencing of endogenous PTK6 promoted an epithelial phenotype and impaired tumor xenograft growth. In mice, PTEN deficiency caused endogenous active PTK6 to localize at membranes in association with decreased E-cadherin expression. Active PTK6 was detected at membranes in some high-grade human prostate tumors, and PTK6 and E-cadherin expression levels were inversely correlated in human prostate cancers. Additionally, high levels of PTK6 expression predicted poor prognosis in prostate cancer patients. Our findings reveal novel functions for PTK6 in the pathophysiology of prostate cancer, and they define this kinase as a candidate therapeutic target.

PTK6 Inhibition Suppresses Metastases of Triple-Negative Breast Cancer via SNAIL-Dependent E-Cadherin Regulation

“…Overexpression of PTK6 in prostate cancer cells promoted EMT via Akt activation (39). In MCF7 breast cancer cells overexpressing HER2 that were selected in vivo for increased invasive potential, downregulation of PTK6 suppressed migration and expression of mesenchymal markers, and restored E-cadherin expression; these effects were prevented by restoration of active Stat3, a known substrate of PTK6 (40).…”

PTK6/BRK is expressed in the normal mammary gland and activated at the plasma membrane in breast tumors

“…Targeting PTK6 into the nucleus of prostate cancer cells in vitro negatively regulates growth [8]. In human and mouse prostate cancer cells, PTK6 is activated at the cell plasma membrane [9-11]. A number of membrane associated PTK6 substrates, including Paxillin [12], EGFR [13], IGF-1R [14], p130Cas [9], and focal adhesion kinase [10] have been identified.…”

PTK6 (protein tyrosine kinase 6)

“…In prostate cancer cells, targeting PTK6 to the nucleus inhibits proliferation while cytoplasmic PTK6 promotes proliferation . Overexpression of membrane-targeted active PTK6 in prostate cancer cells drives epithelialmesenchymal transition (Zheng et al, 2012) and anchorage-independent survival (Zheng et al, 2013a) as well as in vivo xenograft metastasis (Zheng et al, 2013b). Recently, PTK6 was detected in nuclei of normal mammary gland epithelium (Peng et al, 2014), and overexpression of PTK6 promotes oncogenic signaling and invasive phenotypes in breast cancer cells (Harvey and Crompton, 2003;Xiang et al, 2008;Irie et al, 2010).…”

“…Recently, PTK6 was detected in nuclei of normal mammary gland epithelium (Peng et al, 2014), and overexpression of PTK6 promotes oncogenic signaling and invasive phenotypes in breast cancer cells (Harvey and Crompton, 2003;Xiang et al, 2008;Irie et al, 2010). In human prostate and breast cancers, PTK6 is activated at the plasma membrane (Zheng et al, 2013b;Peng et al, 2014).…”

“…Analysis of Oncomine microarray data showed that PTK6 mRNAs levels are higher in metastatic prostate tumors, and patients with high PTK6 have reduced survival (Zheng et al, 2013b). Knockdown of PTK6 in the human PC3 prostate tumor cell line inhibited xenograft tumor growth (Zheng et al, 2013).…”