ArticleCurrent biology : CB2018
Distinct Interaction Sites of Rac GTPase with WAVE Regulatory Complex Have Non-redundant Functions in Vivo.
Article in Current biology : CB, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 papers.
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Who cites it
56 citing papers in PubMed, 96 citations in OpenAlex.
- Arp2/3 complex-dependent actin remodeling is required for efficient RSV uncoating in A549 cells.Journal of virology · 2026Article
- Profilin promotes lamellipodium protrusion by tuning the antagonistic activities of capping protein and VASP.Nature communications · 2026Article
- Molecular signatures of disulfidptosis: interplay with programmed cell death pathways and therapeutic implications in oncology.Cellular & molecular biology letters · 2025Review
- Survival strategies of cancer cells: the role of macropinocytosis in nutrient acquisition, metabolic reprogramming, and therapeutic targeting.Autophagy · 2025Review
- The WAVE complex in developmental and adulthood brain disorders.Experimental & molecular medicine · 2025Review
- Developmental and Epileptic Encephalopathy: Pathogenesis of Intellectual Disability Beyond Channelopathies.Biomolecules · 2025Review
- Molecular basis of the CYFIP2 and NCKAP1 autism-linked variants in the WAVE regulatory complex.Protein science : a publication of the Protein Society · 2025Article
- AKAP12 Variant 1 Knockout Enhances Vascular Endothelial Cell Motility.Journal of vascular research · 2025Article
- Common characteristics of variants linked to autism spectrum disorder in the WAVE regulatory complex.Frontiers in computational neuroscience · 2025Article
- The WAVE regulatory complex interacts with Boc and is required for Shh-mediated axon guidance.iScience · 2024Article
- Disulfidptosis: a novel cell death modality induced by actin cytoskeleton collapse and a promising target for cancer therapeutics.Cell communication and signaling : CCS · 2024Review
- Actin-nucleation promoting factor N-WASP influences alpha-synuclein condensates and pathology.Cell death & disease · 2024Article
- Scar/WAVE has Rac GTPase-independent functions during cell wound repair.Scientific reports · 2023Article
- Ena/VASP clustering at microspike tips involves lamellipodin but not I-BAR proteins, and absolutely requires unconventional myosin-X.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Regulation of the Scar/WAVE complex in migrating cells: A summary of our understanding.Journal of biosciences · 2023Review
- Arf GTPase activates the WAVE regulatory complex through a distinct binding site.Science advances · 2022Article
- Structures reveal a key mechanism of WAVE regulatory complex activation by Rac1 GTPase.Nature communications · 2022Article
- Molecular Dynamics of CYFIP2 Protein and Its R87C Variant Related to Early Infantile Epileptic Encephalopathy.International journal of molecular sciences · 2022Article
- Lamellipodia-like actin networks in cells lacking WAVE regulatory complex.Journal of cell science · 2022Article
- Dual regulation of the actin cytoskeleton by CARMIL-GAP.Journal of cell science · 2022Article
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Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
Abstract
Cell migration often involves the formation of sheet-like lamellipodia generated by branched actin filaments. The branches are initiated when Arp2/3 complex [1] is activated by WAVE regulatory complex (WRC) downstream of small GTPases of the Rac family [2]. Recent structural studies defined two independent Rac binding sites on WRC within the Sra-1/PIR121 subunit of the pentameric WRC [3, 4], but the functions of these sites in vivo have remained unknown. Here we dissect the mechanism of WRC activation and the in vivo relevance of distinct Rac binding sites on Sra-1, using CRISPR/Cas9-mediated gene disruption of Sra-1 and its paralog PIR121 in murine B16-F1 cells combined with Sra-1 mutant rescue. We show that the A site, positioned adjacent to the binding region of WAVE-WCA mediating actin and Arp2/3 complex binding, is the main site for allosteric activation of WRC. In contrast, the D site toward the C terminus is dispensable for WRC activation but required for optimal lamellipodium morphology and function. These results were confirmed in evolutionarily distant Dictyostelium cells. Moreover, the phenotype seen in D site mutants was recapitulated in Rac1 E31 and F37 mutants; we conclude these residues are important for Rac-D site interaction. Finally, constitutively activated WRC was able to induce lamellipodia even after both Rac interaction sites were lost, showing that Rac interaction is not essential for membrane recruitment. Our data establish that physical interaction with Rac is required for WRC activation, in particular through the A site, but is not mandatory for WRC accumulation in the lamellipodium.
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