Structural analysis of the PTEN:P-Rex2 signaling complex reveals how cancer-associated mutations coordinate to hyperactivate Rac1.

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  • Additional Information
    • Source:
      Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101465400 Publication Model: Electronic Cited Medium: Internet ISSN: 1937-9145 (Electronic) Linking ISSN: 19450877 NLM ISO Abbreviation: Sci Signal Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, D.C. : American Association for the Advancement of Science
    • Subject Terms:
      Guanine Nucleotide Exchange Factors*/metabolism ; Neoplasms*/genetics ; PTEN Phosphohydrolase*/genetics ; PTEN Phosphohydrolase*/metabolism ; rac1 GTP-Binding Protein*/genetics ; rac1 GTP-Binding Protein*/metabolism; Humans ; Mutation ; Phosphatidylinositol 3-Kinases ; Signal Transduction
    • Abstract:
      The dual-specificity phosphatase PTEN functions as a tumor suppressor by hydrolyzing PI(3,4,5)P 3 to PI(4,5)P 2 to inhibit PI3K-AKT signaling and cellular proliferation. P-Rex2 is a guanine nucleotide exchange factor for Rho GTPases and can be activated by Gβγ subunits downstream of G protein-coupled receptor signaling and by PI(3,4,5)P 3 downstream of receptor tyrosine kinases. The PTEN:P-Rex2 complex is a commonly mutated signaling node in metastatic cancer. Assembly of the PTEN:P-Rex2 complex inhibits the activity of both proteins, and its dysregulation can drive PI3K-AKT signaling and cellular proliferation. Here, using cross-linking mass spectrometry and functional studies, we gained mechanistic insights into PTEN:P-Rex2 complex assembly and coinhibition. We found that PTEN was anchored to P-Rex2 by interactions between the PDZ-interacting motif in the PTEN C-terminal tail and the second PDZ domain of P-Rex2. This interaction bridged PTEN across the P-Rex2 surface, preventing PI(3,4,5)P 3 hydrolysis. Conversely, PTEN both allosterically promoted an autoinhibited conformation of P-Rex2 and blocked its binding to Gβγ. In addition, we observed that the PTEN-deactivating mutations and P-Rex2 truncations combined to drive Rac1 activation to a greater extent than did either single variant alone. These insights enabled us to propose a class of gain-of-function, cancer-associated mutations within the PTEN:P-Rex2 interface that uncouple PTEN from the inhibition of Rac1 signaling.
      (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
    • Accession Number:
      0 (Guanine Nucleotide Exchange Factors)
      0 (PREX2 protein, human)
      0 (RAC1 protein, human)
      EC 3.1.3.67 (PTEN Phosphohydrolase)
      EC 3.1.3.67 (PTEN protein, human)
      EC 3.6.5.2 (rac1 GTP-Binding Protein)
    • Publication Date:
      Date Created: 20210505 Date Completed: 20220113 Latest Revision: 20220531
    • Publication Date:
      20231215
    • Accession Number:
      10.1126/scisignal.abc4078
    • Accession Number:
      33947796