RT Journal Article
SR Electronic
T1 Systematic Characterization of RhoGEF/RhoGAP Regulatory Proteins Reveals Organization Principles of Rho GTPase Signaling
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 354316
DO 10.1101/354316
A1 Paul M. Müller
A1 Juliane Rademacher
A1 Richard D. Bagshaw
A1 Keziban M. Alp
A1 Girolamo Giudice
A1 Louise E. Heinrich
A1 Carolin Barth
A1 Rebecca L. Eccles
A1 Marta Sanchez-Castro
A1 Lennart Brandenburg
A1 Geraldine Mbamalu
A1 Monika Tucholska
A1 Lisa Spatt
A1 Celina Wortmann
A1 Maciej T. Czajkowski
A1 Robert-William Welke
A1 Sunqu Zhang
A1 Vivian Nguyen
A1 Trendelina Rrustemi
A1 Philipp Trnka
A1 Kiara Freitag
A1 Brett Larsen
A1 Oliver Popp
A1 Philipp Mertins
A1 Chris Bakal
A1 Anne-Claude Gingras
A1 Olivier Pertz
A1 Frederick P. Roth
A1 Karen Colwill
A1 Tony Pawson
A1 Evangelia Petsalaki
A1 Oliver Rocks
YR 2018
UL http://biorxiv.org/content/early/2018/06/25/354316.abstract
AB 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.