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.
journal_name
Nat Cell Bioljournal_title
Nature cell biologyauthors
Müller PM,Rademacher J,Bagshaw RD,Wortmann C,Barth C,van Unen J,Alp KM,Giudice G,Eccles RL,Heinrich LE,Pascual-Vargas P,Sanchez-Castro M,Brandenburg L,Mbamalu G,Tucholska M,Spatt L,Czajkowski MT,Welke RW,Zhang S,Ngudoi
10.1038/s41556-020-0488-xsubject
Has Abstractpub_date
2020-04-01 00:00:00pages
498-511issue
4eissn
1465-7392issn
1476-4679pii
10.1038/s41556-020-0488-xjournal_volume
22pub_type
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