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PNAS 97 (8): 4233-4238

Copyright © 2000 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / 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 Yuan{ddagger}, Jonathan Wood§, Christopher Ross§, Charles L. Sawyers*,{dagger},¶,||, and Young E. Whang{ddagger}

*Department of Medicine, {dagger}Molecular Biology Institute, and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095; {ddagger}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

Accepted for publication February 8, 2000.

Received for publication December 22, 1999.

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.

|| 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.

Communicated by Owen N. Witte, University of California, Los Angeles, CA

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