Afadin couples RAS GTPases to the polarity rheostat Scribble

Nat Commun. 2022 Aug 5;13(1):4562. doi: 10.1038/s41467-022-32335-8.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Polarity*
  • Microfilament Proteins
  • PDZ Domains
  • ras Proteins*


  • Microfilament Proteins
  • afadin
  • ras Proteins

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