Afadin couples RAS GTPases to the polarity rheostat Scribble.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
05 08 2022
05 08 2022
Historique:
received:
12
11
2021
accepted:
26
07
2022
entrez:
5
8
2022
pubmed:
6
8
2022
medline:
10
8
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 35931706
doi: 10.1038/s41467-022-32335-8
pii: 10.1038/s41467-022-32335-8
pmc: PMC9355967
doi:
Substances chimiques
Microfilament Proteins
0
afadin
0
ras Proteins
EC 3.6.5.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4562Subventions
Organisme : CIHR
Pays : Canada
Informations de copyright
© 2022. The Author(s).
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