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Afadin couples RAS GTPases to the polarity rheostat Scribble

Author

Listed:
  • Marilyn Goudreault

    (Université de Montréal)

  • Valérie Gagné

    (Université de Montréal)

  • Chang Hwa Jo

    (Université de Montréal)

  • Swati Singh

    (Université de Montréal)

  • Ryan C. Killoran

    (Université de Montréal)

  • Anne-Claude Gingras

    (Mount Sinai Hospital
    University of Toronto)

  • Matthew J. Smith

    (Université de Montréal
    Université de Montréal)

Abstract

AFDN/Afadin is required for establishment and maintenance of cell-cell contacts and is a unique effector of RAS GTPases. The biological consequences of RAS complex with AFDN are unknown. We used proximity-based proteomics to generate an interaction map for two isoforms of AFDN, identifying the polarity protein SCRIB/Scribble as the top hit. We reveal that the first PDZ domain of SCRIB and the AFDN FHA domain mediate a direct but non-canonical interaction between these important adhesion and polarity proteins. Further, the dual RA domains of AFDN have broad specificity for RAS and RAP GTPases, and KRAS co-localizes with AFDN and promotes AFDN-SCRIB complex formation. Knockout of AFDN or SCRIB in epithelial cells disrupts MAPK and PI3K activation kinetics and inhibits motility in a growth factor-dependent manner. These data have important implications for understanding why cells with activated RAS have reduced cell contacts and polarity defects and implicate AFDN as a genuine RAS effector.

Suggested Citation

  • Marilyn Goudreault & Valérie Gagné & Chang Hwa Jo & Swati Singh & Ryan C. Killoran & Anne-Claude Gingras & Matthew J. Smith, 2022. "Afadin couples RAS GTPases to the polarity rheostat Scribble," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32335-8
    DOI: 10.1038/s41467-022-32335-8
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    References listed on IDEAS

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