Journal
NATURE CELL BIOLOGY
Volume 22, Issue 4, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41556-020-0488-x
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Funding
- Human Frontier Science Program [LT000759/2008-L]
- Helmholtz Young Investigator Program [VH-NG-737]
- CIHR
- Cancer Research UK (CRUK) Programme Foundation Award [C37275/A20146]
- Stand Up to Cancer campaign for Cancer Research UK
- Genome Canada through Ontario Genomics
- Ontario Government (ORF) [GL2-025]
- Terry Fox Research Institute
- Ontario Genomics [OGI-139]
- Canada Excellence Research Chairs Program
- Krembil Foundation
- Avon Foundation
- NIH/NHGRI Center of Excellence in Genomic Science program [HG004233]
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Muller et al. provide a comprehensive resource depicting cellular substrates, localization and interacting partners of RhoGEF and RhoGAP proteins regulating the canonical Rho family of GTPases. 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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