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Activation of the PI3K Pathway in Cancer Through Inhibition of PTEN by Exchange Factor P-REX2a
12 auth. B. Fine, Cindy Hodakoski, Susan Koujak, T. Su, L. Saal, M. Maurer, ...
Reigning In Tumor Suppression Mitogenic signaling through phosphoinositide-3 kinase generates the lipid second messenger phosphatidyl inositol 3,4,5-trisphosphate (PIP3). The tumor suppressor gene product and lipid phosphatase PTEN (phosphatase and …
Reigning In Tumor Suppression Mitogenic signaling through phosphoinositide-3 kinase generates the lipid second messenger phosphatidyl inositol 3,4,5-trisphosphate (PIP3). The tumor suppressor gene product and lipid phosphatase PTEN (phosphatase and tensin homolog on chromosome 10) opposes such mitogenic signaling by dephosphorylating PIP3. In a screen for proteins that interact with PTEN, Fine et al. (p. 1261) identified P-REX2a, a guanine nucleotide exchange factor (GEF) for the RAC small guanosine triphosphatase. Endogenous P-REX2a and PTEN interacted in human embryonic kidney 293 cells, and P-REX2a inhibited catalytic activity of PTEN. Thus, like that of many protein phosphatases, the activity of PTEN is kept in check by an interacting protein inhibitor. P-REX2a thus provides a mechanism through which tumor cells may inactivate PTEN. Cancer cell growth is stimulated by the inhibition of a previously unknown step in cell signaling for tumor suppression. PTEN (phosphatase and tensin homolog on chromosome 10) is a tumor suppressor whose cellular regulation remains incompletely understood. We identified phosphatidylinositol 3,4,5-trisphosphate RAC exchanger 2a (P-REX2a) as a PTEN-interacting protein. P-REX2a mRNA was more abundant in human cancer cells and significantly increased in tumors with wild-type PTEN that expressed an activated mutant of PIK3CA encoding the p110 subunit of phosphoinositide 3-kinase subunit α (PI3Kα). P-REX2a inhibited PTEN lipid phosphatase activity and stimulated the PI3K pathway only in the presence of PTEN. P-REX2a stimulated cell growth and cooperated with a PIK3CA mutant to promote growth factor–independent proliferation and transformation. Depletion of P-REX2a reduced amounts of phosphorylated AKT and growth in human cell lines with intact PTEN. Thus, P-REX2a is a component of the PI3K pathway that can antagonize PTEN in cancer cells.
Published in
Science
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22
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7 | 2009 |
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