Activation of the PI3K Pathway in Cancer Through Inhibition of PTEN by Exchange Factor P-REX2a

作者：Fine Barry; Hodakoski Cindy; Koujak Susan; Su Tao; Saal Lao H; Maurer Matthew; Hopkins Benjamin; Keniry Megan; Sulis Maria Luisa; Mense Sarah; Hibshoosh Hanina; Parsons Ramon^*

来源：Science, 2009, 325(5945): 1261-1265.

DOI：10.1126/science.1173569

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 (PI3K alpha). 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.

• 出版日期2009-9-4