PTK6 activation at the membrane regulates epithelial-mesenchymal transition in prostate cancer

Yu Zheng, Zebin Wang, Wenjun Bie, Patrick M. Brauer, Bethany E. Perez White, Jing Li, Veronique Nogueira, Pradip Raychaudhuri, Nissim Hay, Debra A. Tonetti, Virgilia Macias, André Kajdacsy-Balla, Angela L. Tyner*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

The intracellular tyrosine kinase protein tyrosine kinase 6 (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. In addition, high levels of PTK6 expression predicted poor prognosis in patients with prostate cancer. Our findings reveal novel functions for PTK6 in the pathophysiology of prostate cancer, and they define this kinase as a candidate therapeutic target.

Original languageEnglish (US)
Pages (from-to)5426-5437
Number of pages12
JournalCancer Research
Volume73
Issue number17
DOIs
StatePublished - Sep 1 2013

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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