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

Xinyi Wu, Karin Hepner, Shobha Castelino-Prabhu, Duc Do, Marc B. Kaye, Xiu Juan Yuan, Jonathan Wood, Christopher Ross, Charles L. Sawyers, Young E. Whang

Research output: Contribution to journalArticle

Abstract

PTEN is a tumor suppressor gene mutated in human cancers. Although many mutations target the phosphatase domain, others create a truncated protein lacking 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 [AIP-1 (atrophin interacting protein 1), renamed MAGI-2 (membrane associated guanylate kinase inverted-2)]. MAGI-2 contains eight potential protein-protein interaction domains and is localized to tight junctions in the membrane of epithelial cells. PTEN binds to MAGI-2 through an interaction between the PDZ-binding motif of PTEN and the second PDZ domain of MAGI-2. MAGI-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 MAGI-2 improves the efficiency of PTEN signaling through assembly of a multiprotein complex at the cell membrane.

Original languageEnglish (US)
Pages (from-to)4233-4238
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume97
Issue number8
DOIs
StatePublished - Apr 11 2000

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