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The dual Ras Association (RA) Domains of Drosophila Canoe have differential roles in linking cell junctions to the cytoskeleton during morphogenesis
Open accessPreprint — published as 10.1242/jcs.263546 · Paper page
Abstract
During embryonic development and adult homeostasis epithelial cells must change shape and move without disrupting the tissue’s dynamic architecture. This requires robust linkage of cell-cell adherens junctions to the force-generating actomyosin cytoskeleton. Drosophila Canoe and mammalian Afadin play key roles in this linkage. One central task for the field is defining how upstream inputs from Ras-family GTPases regulate Canoe and Afadin. They are unusual in that they share two tandem Ras-association (RA) domains, which, when deleted, virtually eliminate Canoe function. Previous work in vitro suggested RA1 and RA2 differ in their ability to bind GTPases, but their individual functions in vivo remain unknown. Combining bioinformatic and biochemical approaches, we find that both RA1 and RA2 bind to active Rap1 with similar affinities, and that conserved N-terminal extensions play a role in binding. We created Drosophila canoe mutants to test RA1 and RA2 function in vivo. Despite their similar affinities for Rap1, RA1 and RA2 play strikingly different roles. Deleting RA1 virtually eliminates Canoe function in morphogenesis, while mutants lacking RA2 are viable and fertile but have defects in junctional reinforcement in embryos and during pupal eye development. These data significantly expand our understanding of how adherens junction:cytoskeletal linkage is regulated.
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Metadata
- Authors
- McParland, E. D., Gurley, N. J., Wolfsberg, L. R., Butcher, T. A., Bhattarai, A., Jensen, C. C., Johnson, R. I., Slep, K. C., & Peifer, M.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Wesleyan University (US)
- Corresponding author
- Slep, Kevin C.
- Peifer, Mark
- ORCID
- Venue
- Journal of Cell Science
- Publisher
- openRxiv
- Published
- 2024-07-29
- Volume
- 137
- Issue
- 23
- ISSN
- 0021-9533 (ISSN-L)
- OpenAlex
- W4403768074
- Cited by
- 6
- References
- 1
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 1
- FWCI
- 0.82
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Cell Science (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, cc-by)
- Funders
- National Institutes of Health
- University of North Carolina at Chapel Hill
- National Institute of General Medical Sciences (R15GM114729, R35GM118096)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Keywords
- canoes, afadin, Ras association domain, Rap1, adherens junctions, actomyosin cytoskeleton, cell shape changes, cell migration, Drosophila embryo
- MeSH terms
- Protein Domains, Animals, Cytoskeleton, Drosophila melanogaster, Intercellular Junctions, Morphogenesis, Protein Binding, ras Proteins, Adherens Junctions, Drosophila Proteins
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