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; ... (2020). Systems analysis of RhoGEF and RhoGAP regulatory proteins reveals spatially organized RAC1 signalling from integrin adhesions. Nature cell biology, 22(4), pp. 498-511. Springer Nature 10.1038/s41556-020-0488-x
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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.
Item Type: |
Journal Article (Original Article) |
|---|---|
Division/Institute: |
08 Faculty of Science > Department of Biology > Institute of Cell Biology 09 Interdisciplinary Units > Microscopy Imaging Center (MIC) |
UniBE Contributor: |
van Unen, Jakobus, Pertz, Olivier |
Subjects: |
500 Science > 570 Life sciences; biology |
ISSN: |
1476-4679 |
Publisher: |
Springer Nature |
Language: |
English |
Submitter: |
Olivier Pertz |
Date Deposited: |
31 May 2021 11:02 |
Last Modified: |
05 Dec 2022 15:51 |
Publisher DOI: |
10.1038/s41556-020-0488-x |
PubMed ID: |
32203420 |
BORIS DOI: |
10.48350/156473 |
URI: |
https://boris.unibe.ch/id/eprint/156473 |
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