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.
Highlights
PTEN activity is often lost in prostate cancer
Earlier we reported that conditional disruption of Pten in the mouse prostate led to activating phosphorylation of membrane-associated PTK614 supporting our hypothesis that PTEN may directly negatively regulate PTK6 activity and/or membrane localization in human prostate cancer cells
The phosphatase activity of PTEN is required for the inhibition of active PTK6, as phosphatase-deficient PTEN-G129R has no effect on PTK6 activation status
Summary
PTEN activity is often lost in prostate cancer. We show that the tyrosine kinase PTK6 (BRK) is a PTEN substrate. Introduction of PTEN into a PTEN null prostate cancer cell line leads to dephosphorylation of PY342 but not PY447 and PTK6 inhibition. 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. Activation of PTK6 at the plasma membrane promotes the epithelial mesenchymal transition (EMT) and survival and metastasis of prostate tumor cells in xenograft models[14]. Activation of PTK6 at the plasma membrane has been observed in human prostate[14], breast[16] and skin tumors[8]
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