Systems analysis of RhoGEF and RhoGAP regulatory proteins reveals spatially organized RAC1 signalling from integrin adhesions

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Item Type:	Article
Title:	Systems analysis of RhoGEF and RhoGAP regulatory proteins reveals spatially organized RAC1 signalling from integrin adhesions
Creators Name:	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. and Rocks, O.
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:	COS Cells, Cell Adhesion, Cell Line, Cell Movement, Cellular Mechanotransduction, Chlorocebus aethiops, Computational Biology, Cytoskeleton, Fibroblasts, GTPase-Activating Proteins, Gene Expression Profiling, Gene Expression Regulation, HEK293 Cells, HeLa Cells, Integrins, Madin Darby Canine Kidney Cells, Pan troglodytes, Protein Domains, Rho Guanine Nucleotide Exchange Factors, rac1 GTP-Binding Protein, Animals, Dogs, Mice, Rats
Source:	Nature Cell Biology
ISSN:	1465-7392
Publisher:	Nature Publishing Group
Volume:	22
Number:	4
Page Range:	498-511
Date:	April 2020
Official Publication:	https://doi.org/10.1038/s41556-020-0488-x
PubMed:	View item in PubMed

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