Interaction of the tumor suppressor PTEN/MMAC with a PDZ domain of MAGI3, a novel membrane-associated guanylate kinase

PTEN/MMAC is a Phosphatase that is mutated in multiple human tumors. PTEN/MMAC dephosphorylates 3-phosphorylated phosphatidylinositol phosphates that activate Akt/protein kinase B (PKB) kinase activity. Akt/PKB is implicated in the inhibition of Apoptosis, and cell lines and tumors with mutated PTEN/MMAC show increased Akt/PKB kinase activity and resistance to Apoptosis. PTEN/MMAC contains a PDZ domain-binding site, and we show here that the Phosphatase binds to a PDZ domain of membrane-associated guanylate kinase with inverted orientation (MAGI) 3, a novel inverted membrane-associated guanylate kinase that localizes to epithelial cell tight junctions. Importantly, MAGI3 and PTEN/MMAC cooperate to modulate the kinase activity of Akt/PKB. These data suggest that MAGI3 allows for the juxtaposition of PTEN/MMAC to phospholipid signaling pathways involved with cell survival.