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PNAS 97 (8): 4233-4238

Copyright © 2000 by the National Academy of Sciences.

Vol. 97, Issue 8, 4233-4238, April 11, 2000

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

Xinyi Wu*,dagger , Karin Hepner*,dagger , Shobha Castelino-Prabhu*, Duc Do*, Marc B. Kaye*, Xiu-Juan YuanDagger , Jonathan Wood§, Christopher Ross§, Charles L. Sawyers*,dagger ,,||, and Young E. WhangDagger

* Department of Medicine, dagger  Molecular Biology Institute, and  Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095; Dagger  Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599; and § Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21205

Communicated by Owen N. Witte, University of California, Los Angeles, CA, February 8, 2000 (received for review December 22, 1999)

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.

|| To whom reprint requests should be addressed at: 11-934 Factor, UCLA-Hematology/Oncology, 10833 Le Conte Avenue, Los Angeles, CA 90095. E-mail: csawyers{at}mednet.ucla.edu.

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