Systems analysis of RhoGEF and RhoGAP regulatory proteins reveals spatially organized RAC1 signalling from integrin adhesions
- 23 March 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 22 (4), 498-511
- https://doi.org/10.1038/s41556-020-0488-x
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.Keywords
Funding Information
- 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)
This publication has 89 references indexed in Scilit:
- Rho protein crosstalk: another social network?Trends in Cell Biology, 2011
- A Novel Spatiotemporal RhoC Activation Pathway Locally Regulates Cofilin Activity at InvadopodiaCurrent Biology, 2011
- COMPASS: A suite of pre‐ and post‐search proteomics software tools for OMSSAProteomics, 2011
- ProHits: integrated software for mass spectrometry–based interaction proteomicsNature Biotechnology, 2010
- The Amino Acid Motif L/IIxxFE Defines a Novel Actin-Binding Sequence in PDZ-RhoGEFBiochemistry, 2009
- MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantificationNature Biotechnology, 2008
- Functional atlas of the integrin adhesomeNature, 2007
- GEFs and GAPs: Critical Elements in the Control of Small G ProteinsCell, 2007
- Structural Mechanism for Lipid Activation of the Rac-Specific GAP, β2-ChimaerinCell, 2004
- IntAct: an open source molecular interaction databaseNucleic Acids Research, 2004