TY - JOUR T1 - Systematic Characterization of RhoGEF/RhoGAP Regulatory Proteins Reveals Organization Principles of Rho GTPase Signaling JF - bioRxiv DO - 10.1101/354316 SP - 354316 AU - Paul M. Müller AU - Juliane Rademacher AU - Richard D. Bagshaw AU - Keziban M. Alp AU - Girolamo Giudice AU - Louise E. Heinrich AU - Carolin Barth AU - Rebecca L. Eccles AU - Marta Sanchez-Castro AU - Lennart Brandenburg AU - Geraldine Mbamalu AU - Monika Tucholska AU - Lisa Spatt AU - Celina Wortmann AU - Maciej T. Czajkowski AU - Robert-William Welke AU - Sunqu Zhang AU - Vivian Nguyen AU - Trendelina Rrustemi AU - Philipp Trnka AU - Kiara Freitag AU - Brett Larsen AU - Oliver Popp AU - Philipp Mertins AU - Chris Bakal AU - Anne-Claude Gingras AU - Olivier Pertz AU - Frederick P. Roth AU - Karen Colwill AU - Tony Pawson AU - Evangelia Petsalaki AU - Oliver Rocks Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/06/25/354316.abstract N2 - 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. ER -