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Systematic characterization of RhoGEF/RhoGAP regulatory proteins reveals organization principles of Rho GTPase signaling

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Item Type:Preprint
Title:Systematic characterization of RhoGEF/RhoGAP regulatory proteins reveals organization principles of Rho GTPase signaling
Creators Name:Müller, P.M. and Rademacher, J. and Bagshaw, R.D. and Alp, K.M. and Giudice, G. and Heinrich, L.E. and Barth, C. and Eccles, R.L. and Sanchez-Castro, M. and Brandenburg, L. and Mbamalu, G. and Tucholska, M. and Spatt, L. and Wortmann, C. and Czajkowski, M.T. and Welke, R.W. and Zhang, S. and Nguyen, V. and Rrustemi, T. and Trnka, P. and Freitag, K. and Larsen, B. and Popp, O. and Mertins, P. and Bakal, C. and Gingras, A.C. and Pertz, O. and Roth, F.P. and Colwill, K. and Pawson, T. and Petsalaki, E. and Rocks, O.
Abstract:Rho GTPases control cell shape formation and thus fundamental physiological processes in all eukaryotes. Their functions are regulated by 145 RhoGEF and RhoGAP multi-domain proteins in humans. To provide the framework for a systems-level understanding of how these regulators orchestrate cellular morphogenesis, we comprehensively characterized their substrate specificities, localization and interactome. The resulting resource places the RhoGEFs/RhoGAPs in functional context, serving as a foundation for targeted and integrated studies. Our data reveals their critical role in the spatial organization of Rho signaling. They localize to multiple compartments to provide positional information, are extensively interconnected to jointly coordinate their signaling networks and are widely autoinhibited to remain sensitive to local activation. RhoGAPs exhibit lower substrate specificity than RhoGEFs and may contribute to preserving Rho activity gradients. We demonstrate the utility of our integrated data by detailing a multi-RhoGEF complex downstream of G-protein-coupled receptors in which the enzymes mutually regulate their activities.
Source:bioRxiv
Publisher:Cold Spring Harbor Laboratory (U.S.A.)
Article Number:354316
Date:25 June 2018
Official Publication:https://doi.org/10.1101/354316

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