Activation of the PI3K pathway in cancer through inhibition of PTEN by exchange factor P-REX2a.
basic_science · Level V
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- Record sourced from PubMed, PMID 19729658.
- Also identified by DOI 10.1126/science.1173569 and PMC identifier 2936784.
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Abstract
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 alpha (PI3Kalpha). 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.
Medical subject headings
- GTPase-Activating Proteins
- Neoplasms
- PTEN Phosphohydrolase
- Phosphatidylinositol 3-Kinases