Systems analysis of RhoGEF and RhoGAP regulatory proteins reveals spatially organized RAC1 signalling from integrin adhesions
| Autor: | Müller, Paul M, Rademacher, Juliane, Bagshaw, Richard D, Wortmann, Celina, Barth, Carolin, van Unen, Jakobus, Alp, Keziban M, Giudice, Girolamo, Eccles, Rebecca L, Heinrich, Louise E, Pascual-Vargas, Patricia, Sanchez-Castro, Marta, Brandenburg, Lennart, Mbamalu, Geraldine, Tucholska, Monika, Spatt, Lisa, Czajkowski, Maciej T, Welke, Robert-William, Zhang, Sunqu, Nguyen, Vivian, Rrustemi, Trendelina, Trnka, Philipp, Freitag, Kiara, Larsen, Brett, Popp, Oliver, Mertins, Philipp, Gingras, Anne-Claude, Roth, Frederick P, Colwill, Karen, Bakal, Chris, Pertz, Olivier, Pawson, Tony, Petsalaki, Evangelia, Rocks, Oliver |
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| Rok vydání: | 2020 |
| Předmět: |
rac1 GTP-Binding Protein
Integrins Pan troglodytes Mechanotransduction Cellular Cell Line Madin Darby Canine Kidney Cells Mice Dogs Protein Domains Cell Movement Chlorocebus aethiops Cell Adhesion Animals Humans Cytoskeleton Gene Expression Profiling GTPase-Activating Proteins Computational Biology Fibroblasts Rats HEK293 Cells Gene Expression Regulation COS Cells 570 Life sciences biology Rho Guanine Nucleotide Exchange Factors HeLa Cells |
| DOI: | 10.48350/156473 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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