Evidence for regulation of the PTEN tumor suppressor by a membrane-localized multi-PDZ domain containing scaffold protein MAGl-2

摘要

PTEN is a tumor suppressor gene mutated in human cancers. Although many mutations target the phosphatase domain, others create a truncated protein Iacking the C-terminal PDZ-binding motif or a protein that extends beyond the PDZ-binding motif. Using the yeast two-hybrid system, we isolated a membrane- associated guanylate kinase family protein with multiple PDZ domains lAIP-1 (atrophin interacting protein 1). renamed MAGl-2 (membrane associated guanylate kinase inverted-2)l. MAGl-2 con- tains eight potential protein-protein interaction domains and is localized to tight junctions in the membrane of epithelial cells. PTEN binds to MAGl-2 through an interaction between the PDZ- binding motif of PTEN and the second PDZ domain of MAGl-2. MAGl-2 enhances the ability of PTEN to suppress Akt activation. Furthermore. certain PTEN mutants have reduced stability, which is restored by adding the minimal PDZ-binding motif back to the truncated protein. We propose that MAGl-2 improves the effi- ciency of PTEN signaling through assembly of a multiprotein complex at the cell membrane.