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

Proc Natl Acad Sci U S A. 2000 Apr 11;97(8):4233-8. doi: 10.1073/pnas.97.8.4233.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Gene Expression Regulation / genetics*
  • Genes, Tumor Suppressor*
  • Guanylate Kinases
  • Humans
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Nucleoside-Phosphate Kinase / genetics*
  • Nucleoside-Phosphate Kinase / metabolism
  • PTEN Phosphohydrolase
  • Phosphoric Monoester Hydrolases / genetics*
  • Phosphoric Monoester Hydrolases / metabolism
  • Protein Binding
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins*
  • Tumor Suppressor Proteins*

Substances

  • Membrane Proteins
  • Proto-Oncogene Proteins
  • Tumor Suppressor Proteins
  • AKT1 protein, human
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Nucleoside-Phosphate Kinase
  • Guanylate Kinases
  • Phosphoric Monoester Hydrolases
  • PTEN Phosphohydrolase
  • PTEN protein, human