PTEN is a protein phosphatase that targets active PTK6 and inhibits PTK6 oncogenic signaling in prostate cancer

Darren J. Wozniak, Andre Kajdacsy-Balla, Virgilia Macias, Susan Ball-Kell, Morgan L. Zenner, Wenjun Bie and Angela L. Tyner ()
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Darren J. Wozniak: Departments of Biochemistry and Molecular Genetics
Andre Kajdacsy-Balla: University of Illinois
Virgilia Macias: University of Illinois
Susan Ball-Kell: Global Path Imaging and Consulting, Ltd.
Morgan L. Zenner: Departments of Biochemistry and Molecular Genetics
Wenjun Bie: Departments of Biochemistry and Molecular Genetics
Angela L. Tyner: Departments of Biochemistry and Molecular Genetics

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract PTEN activity is often lost in prostate cancer. We show that the tyrosine kinase PTK6 (BRK) is a PTEN substrate. Phosphorylation of PTK6 tyrosine 342 (PY342) promotes activation, while phosphorylation of tyrosine 447 (PY447) regulates auto-inhibition. Introduction of PTEN into a PTEN null prostate cancer cell line leads to dephosphorylation of PY342 but not PY447 and PTK6 inhibition. Conversely, PTEN knockdown promotes PTK6 activation in PTEN positive cells. Using a variety of PTEN mutant constructs, we show that protein phosphatase activity of PTEN targets PTK6, with efficiency similar to PTP1B, a phosphatase that directly dephosphorylates PTK6 Y342. Conditional disruption of Pten in the mouse prostate leads to tumorigenesis and increased phosphorylation of PTK6 Y342, and disruption of Ptk6 impairs tumorigenesis. In human prostate tumor tissue microarrays, loss of PTEN correlates with increased PTK6 PY342 and poor outcome. These data suggest PTK6 activation promotes invasive prostate cancer induced by PTEN loss.

Date: 2017
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DOI: 10.1038/s41467-017-01574-5

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