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/M MAC 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. P TEN/MMAC contains a PDZ domain-binding site, and we show here that the phos phatase binds to a PDZ domain of membrane-associated guanylate kinase with inverted orientation (MAGI) 3, a novel inverted membrane-associated guanyla te kinase that localizes to epithelial cell tight junctions. Importantly, M AGI3 and PTEN/MMAC cooperate to modulate the kinase activity of AKT/PKB. Th ese data suggest that MAGIS allows for the juxtaposition of PTEN/MMAC to ph ospholipid signaling pathways involved with cell survival.