brane in Glioblastoma Contributes to PTEN Inactivation

ownload blastoma multiforme (GBM) is a severe brain malignancy with limited treatment and dismal prognosis. mor suppressor PTEN, a major inhibitor of the phosphatidylinositol-3-OH kinase (PI3K)/Akt pathway, is ntly deleted in GBM tumors. PTEN antagonizes PI3K by dephosphorylating PI3K phosphoinositide subat the plasma membrane. The PTEN binding adapter protein NHERF1/EBP50 is overexpressed in GBM effects on tumorigenesis have yet to be determined. Here, we show that NHERF1 is localized to the a membrane in normal astrocytes and to the cytoplasm of GBM tumor cells. This cytoplasmic shift led an altered membrane distribution of wild-type PTEN with consecutive Akt activation. Membrane eting of NHERF1 in GBM cells recruited PTEN to the membrane and suppressed Akt activation and cell ration. Conversely, NHERF1 depletion in GBM cells with membrane-localized NHERF1 increased cell ration and Akt activation. Our findings define a tumor suppressor role for NHERF1 at the plasma memprolife brane, and reveal a novel mechanism for PI3K/Akt activation through PTEN inactivation caused by a loss of membrane-localized NHERF1. Cancer Res; 70(17); 6697–703. ©2010 AACR.

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