| Abstract |
The tumor suppressor activity of PTEN is mostly attributed to its lipid phosphatase activity, antagonizing the
PI3K signaling. Reduced or lost activity of PTEN is often detected in cancer cells, contributing to constitutive
PI3K pathway and downstream promotion of cell survival and proliferation. Overall the regulation of PTEN
activity by various mechanisms is not well understood. Posttranslational modification of PTEN by tyrosine
phosphorylation has been reported, however, the mechanism remain elusive. The inhibitory effect of PTEN on
PI3K signaling does not discriminate among the different PI3K isoforms, however, p110 isoform was found to
inactivate PTEN through a pathway involving RhoA with the latter to induce the tyrosine phosphorylation of
PTEN. In the present study we have used genetic and pharmacological approaches and cell-free assays to dissect
the mechanism of RhoA-induced tyrosine phosphorylation and activation of PTEN downstream of p110 PI3K.
FAK is a cytoplasmic tyrosine kinase that has been shown to play critical roles in development of human cancer.
We now show that FAK phosphorylates and activates PTEN and that the regulation of FAK is under the negative
control of p110PI3K and under the positive regulation of RhoA and ROCK. Indeed, the phosphorylation of
FAK was unexpectedly increased in macrophages derived from mice expressing kinase-dead p110 while the
phosphorylation of FAK was decreased in macrophages derived from mice expressing constitutively active
p110. Pharmacological inactivation of RhoA or ROCK reduced the phosphorylation of FAK to normal levels in
cells with genetically inactivated p110. Likewise, pharmacological inactivation of FAK restored the functional
defects of p110 inactivation, including Akt phosphorylation and cell proliferation, and in parallel reduced the
phosphorylation and activity of PTEN. Collectively, this work identifies FAK as a target of p110 PI3K that links
RhoA with PTEN and establishes for the first time that PTEN is a substrate of FAK for tyrosine phosphorylation.
Our data show a novel mechanism of PTEN regulation and provide new information for the biological roles of
FAK. The important role of PTEN activity in cell growth together with the fact that FAK inhibitors have been
developed as anti-proliferative agents raise the question if the efficacy of FAK inhibition might be
counterbalanced by the PTEN inhibition.
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FAK regulates PTEN under the control of p110δ P13 kinase
