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.
Wu
Y
Y
Departments of Molecular Oncology and Molecular Biology, Genentech, Inc., South San Francisco, California 94080, USA.
Dowbenko
D
D
Spencer
S
S
Laura
R
R
Lee
J
J
Gu
Q
Q
Lasky
L A
LA
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D017124:Conserved Sequence; D004847:Epithelial Cells / Q000201:enzymology; D005260:Female; D016153:Genes, Suppressor; D051528:Guanylate Kinases; D006801:Humans; D008297:Male; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D009703:Nucleoside-Phosphate Kinase / Q000737:chemistry* / Q000378:metabolism*; D009928:Organ Specificity; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012441:Saccharomyces cerevisiae; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D019108:Tight Junctions / Q000201:enzymology; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
C496469:MAGI3 protein, human; D008565:Membrane Proteins; D011994:Recombinant Proteins; D025521:Tumor Suppressor Proteins; D009703:Nucleoside-Phosphate Kinase; D051528:Guanylate Kinases; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human