Afadin couples RAS GTPases to the polarity rheostat Scribble

Marilyn Goudreault, Valérie Gagné, Chang Hwa Jo, Swati Singh, Ryan C. Killoran, Anne-Claude Gingras and Matthew J. Smith ()
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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
Matthew J. Smith: Université de Montréal

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: 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.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32335-8

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DOI: 10.1038/s41467-022-32335-8

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