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Systematic Characterization of RhoGEF/RhoGAP Regulatory Proteins Reveals Organization Principles of Rho GTPase Signaling

Paul M. Müller, Juliane Rademacher, Richard D. Bagshaw, Keziban M. Alp, Girolamo Giudice, Louise E. Heinrich, Carolin Barth, Rebecca L. Eccles, Marta Sanchez-Castro, Lennart Brandenburg, Geraldine Mbamalu, Monika Tucholska, Lisa Spatt, Celina Wortmann, Maciej T. Czajkowski, Robert-William Welke, Sunqu Zhang, Vivian Nguyen, Trendelina Rrustemi, Philipp Trnka, Kiara Freitag, Brett Larsen, Oliver Popp, Philipp Mertins, Chris Bakal, Anne-Claude Gingras, Olivier Pertz, Frederick P. Roth, Karen Colwill, Tony Pawson, Evangelia Petsalaki, View ORCID ProfileOliver Rocks
doi: https://doi.org/10.1101/354316
Paul M. Müller
1Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10,13125 Berlin, Germany
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Juliane Rademacher
1Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10,13125 Berlin, Germany
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Richard D. Bagshaw
2Lunenfeld-Tanenbaum Research Institute, Sinai Health System, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada
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Keziban M. Alp
1Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10,13125 Berlin, Germany
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Girolamo Giudice
3EMBL-EBI, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB101SD, UK
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Louise E. Heinrich
5Institute for Cancer Research, Chester Beatty Laboratories, 237 Fulham Road. London SW7 3RP, UK
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Carolin Barth
1Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10,13125 Berlin, Germany
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Rebecca L. Eccles
1Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10,13125 Berlin, Germany
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Marta Sanchez-Castro
2Lunenfeld-Tanenbaum Research Institute, Sinai Health System, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada
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Lennart Brandenburg
1Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10,13125 Berlin, Germany
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Geraldine Mbamalu
2Lunenfeld-Tanenbaum Research Institute, Sinai Health System, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada
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Monika Tucholska
2Lunenfeld-Tanenbaum Research Institute, Sinai Health System, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada
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Lisa Spatt
1Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10,13125 Berlin, Germany
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Celina Wortmann
1Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10,13125 Berlin, Germany
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Maciej T. Czajkowski
1Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10,13125 Berlin, Germany
4Berlin Institute of Health (BIH), Kapelle-Ufer 2,10117 Berlin, Germany
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Robert-William Welke
1Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10,13125 Berlin, Germany
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Sunqu Zhang
2Lunenfeld-Tanenbaum Research Institute, Sinai Health System, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada
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Vivian Nguyen
2Lunenfeld-Tanenbaum Research Institute, Sinai Health System, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada
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Trendelina Rrustemi
1Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10,13125 Berlin, Germany
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Philipp Trnka
1Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10,13125 Berlin, Germany
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Kiara Freitag
1Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10,13125 Berlin, Germany
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Brett Larsen
2Lunenfeld-Tanenbaum Research Institute, Sinai Health System, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada
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Oliver Popp
1Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10,13125 Berlin, Germany
4Berlin Institute of Health (BIH), Kapelle-Ufer 2,10117 Berlin, Germany
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Philipp Mertins
1Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10,13125 Berlin, Germany
4Berlin Institute of Health (BIH), Kapelle-Ufer 2,10117 Berlin, Germany
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Chris Bakal
5Institute for Cancer Research, Chester Beatty Laboratories, 237 Fulham Road. London SW7 3RP, UK
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Anne-Claude Gingras
2Lunenfeld-Tanenbaum Research Institute, Sinai Health System, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada
7Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
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Olivier Pertz
6Institute of Cell Biology, University of Bern, Baltzerstrasse 4 6, 3012 Bern, Switzerland
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Frederick P. Roth
2Lunenfeld-Tanenbaum Research Institute, Sinai Health System, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada
8Donnelly Centre and Departments of Molecular Genetics and Computer Science, University of Toronto, Toronto, Ontario M5S 3E1, Canada
9Canadian Institute for Advanced Research, Toronto, Ontario M5G1Z8, Canada
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Karen Colwill
2Lunenfeld-Tanenbaum Research Institute, Sinai Health System, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada
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Tony Pawson
2Lunenfeld-Tanenbaum Research Institute, Sinai Health System, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada
7Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
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Evangelia Petsalaki
2Lunenfeld-Tanenbaum Research Institute, Sinai Health System, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada
3EMBL-EBI, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB101SD, UK
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  • For correspondence: petsalaki@ebi.ac.uk
Oliver Rocks
1Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10,13125 Berlin, Germany
2Lunenfeld-Tanenbaum Research Institute, Sinai Health System, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada
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  • ORCID record for Oliver Rocks
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Summary

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.

Footnotes

  • ↵† Deceased

  • ↵++ Lead Contact: oliver.rocks{at}mdc-berlin.de (O.R.)

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted June 25, 2018.
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Systematic Characterization of RhoGEF/RhoGAP Regulatory Proteins Reveals Organization Principles of Rho GTPase Signaling
Paul M. Müller, Juliane Rademacher, Richard D. Bagshaw, Keziban M. Alp, Girolamo Giudice, Louise E. Heinrich, Carolin Barth, Rebecca L. Eccles, Marta Sanchez-Castro, Lennart Brandenburg, Geraldine Mbamalu, Monika Tucholska, Lisa Spatt, Celina Wortmann, Maciej T. Czajkowski, Robert-William Welke, Sunqu Zhang, Vivian Nguyen, Trendelina Rrustemi, Philipp Trnka, Kiara Freitag, Brett Larsen, Oliver Popp, Philipp Mertins, Chris Bakal, Anne-Claude Gingras, Olivier Pertz, Frederick P. Roth, Karen Colwill, Tony Pawson, Evangelia Petsalaki, Oliver Rocks
bioRxiv 354316; doi: https://doi.org/10.1101/354316
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Systematic Characterization of RhoGEF/RhoGAP Regulatory Proteins Reveals Organization Principles of Rho GTPase Signaling
Paul M. Müller, Juliane Rademacher, Richard D. Bagshaw, Keziban M. Alp, Girolamo Giudice, Louise E. Heinrich, Carolin Barth, Rebecca L. Eccles, Marta Sanchez-Castro, Lennart Brandenburg, Geraldine Mbamalu, Monika Tucholska, Lisa Spatt, Celina Wortmann, Maciej T. Czajkowski, Robert-William Welke, Sunqu Zhang, Vivian Nguyen, Trendelina Rrustemi, Philipp Trnka, Kiara Freitag, Brett Larsen, Oliver Popp, Philipp Mertins, Chris Bakal, Anne-Claude Gingras, Olivier Pertz, Frederick P. Roth, Karen Colwill, Tony Pawson, Evangelia Petsalaki, Oliver Rocks
bioRxiv 354316; doi: https://doi.org/10.1101/354316

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