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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Darren J. Wozniak & Andre Kajdacsy-Balla & Virgilia Macias & Susan Ball-Kell & Morgan L. Zenner & Wenjun Bie & Angela L. Tyner, 2017. "PTEN is a protein phosphatase that targets active PTK6 and inhibits PTK6 oncogenic signaling in prostate cancer," Nature Communications, Nature, vol. 8(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01574-5
    DOI: 10.1038/s41467-017-01574-5
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