Systems analysis of RhoGEF and RhoGAP regulatory proteins reveals spatially organized RAC1 signalling from integrin adhesions
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Abstract
Rho GTPases are central regulators of the cytoskeleton and, in humans, are controlled by 145 multidomain guanine nucleotide exchange factors (RhoGEFs) and GTPase-activating proteins (RhoGAPs). How Rho signalling patterns are established in dynamic cell spaces to control cellular morphogenesis is unclear. Through a family-wide characterization of substrate specificities, interactomes and localization, we reveal at the systems level how RhoGEFs and RhoGAPs contextualize and spatiotemporally control Rho signalling. These proteins are widely autoinhibited to allow local regulation, form complexes to jointly coordinate their networks and provide positional information for signalling. RhoGAPs are more promiscuous than RhoGEFs to confine Rho activity gradients. Our resource enabled us to uncover a multi-RhoGEF complex downstream of G-protein-coupled receptors controlling CDC42-RHOA crosstalk. Moreover, we show that integrin adhesions spatially segregate GEFs and GAPs to shape RAC1 activity zones in response to mechanical cues. This mechanism controls the protrusion and contraction dynamics fundamental to cell motility. Our systems analysis of Rho regulators is key to revealing emergent organization principles of Rho signalling.
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GEF-H1 is an active RhoGEF.
“Indeed, ARHGEF2/GEF‐H1 is an active RhoGEF [54]; thus, limiting its intrinsic activity is essential to control the contractile homeostasis of the cell.”
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<scp>RhoA</scp> regulation in space and time
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- Authors
- Müller, P. M., Rademacher, J., Bagshaw, R. D., Wortmann, C., Barth, C., van Unen, J., Alp, K. M., Giudice, G., Eccles, R. L., Heinrich, L. E., Pascual-Vargas, P., Sanchez-Castro, M., Brandenburg, L., Mbamalu, G., Tucholska, M., Spatt, L., Czajkowski, M. T., Welke, R.-W., Zhang, S., Nguyen, V., Rrustemi, T., Trnka, P., Freitag, K., Larsen, B., Popp, O., Mertins, P., Gingras, A.-C., Roth, F. P., Colwill, K., Bakal, C., Pertz, O., Pawson, T., Petsalaki, E., & Rocks, O.
- Affiliations
- Max Delbrück Center (DE)
- Lunenfeld-Tanenbaum Research Institute (CA)
- European Bioinformatics Institute (GB)
- Institute of Cancer Research (GB)
- University of Toronto (CA)
- Canadian Institute for Advanced Research (CA)
- University of Bern (CH)
- Corresponding author
- Petsalaki, Evangelia
- Rocks, Oliver
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2020-03-23
- Volume
- 22
- Issue
- 4
- Pages
- 498-511
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- OpenAlex
- W3012860965
- Cited by
- 253
- References
- 3
- Citations by year
- 2026: 30 · 2025: 44 · 2024: 32 · 2023: 48 · 2022: 40 · 2021: 39 · 2020: 17 · 2019: 2 · 2018: 1
- FWCI
- 11.70
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature Cell Biology (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (acceptedVersion)
- BORIS (University Library Bern) (submittedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Funders
- Gouvernement du Canada | Instituts de Recherche en Santé du Canada | CIHR Skin Research Training Centre
- U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (HG004233)
- Canada Excellence Research Chairs, Government of Canada
- Krembil Foundation
- Ontario Genomics Institute (OGI-139)
- EIF | Stand Up To Cancer
- Terry Fox Foundation
- Genome Canada (ORF GL2-025)
- Avon Foundation for Women
- Human Frontier Science Program (LT000759/2008-L)
- Helmholtz Association (VH-NG-737)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- Rho GTPases, RhoGEF, RhoGAP, integrin-mediated adhesion, G protein-coupled receptor signaling, autoinhibition, protein-protein interaction network, cell motility, mechanotransduction, cytoskeleton regulation
- MeSH terms
- Protein Domains, Animals, Cell Adhesion, Cell Line, Cell Movement, Chlorocebus aethiops, Pan troglodytes, Cytoskeleton, Dogs, Fibroblasts, Gene Expression Regulation, HeLa Cells, Humans, Integrins, Computational Biology, COS Cells, GTPase-Activating Proteins, rac1 GTP-Binding Protein, Gene Expression Profiling, Mechanotransduction, Cellular, Mice, Rats, HEK293 Cells, Madin Darby Canine Kidney Cells, Rho Guanine Nucleotide Exchange Factors
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