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Systems analysis of RhoGEF and RhoGAP regulatory proteins reveals spatially organized RAC1 signalling from integrin
Paul M Müller1, Juliane Rademacher1, Richard D Bagshaw2
1Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
Nature Cell Biology
|March 24, 2020
Summary
This study reveals how guanine nucleotide exchange factors (RhoGEFs) and GTPase-activating proteins (RhoGAPs) spatiotemporally control Rho signaling. They form complexes and use substrate specificities to regulate cytoskeleton dynamics for cell morphogenesis.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Rho GTPases are crucial for cytoskeleton regulation.
- 145 human RhoGEFs and RhoGAPs control Rho signaling.
- Mechanisms of Rho signaling patterning in cells remain unclear.
Purpose of the Study:
- To understand how RhoGEFs and RhoGAPs spatiotemporally control Rho signaling.
- To reveal systems-level insights into Rho signaling regulation.
- To elucidate the role of Rho regulators in cellular morphogenesis.
Main Methods:
- Family-wide characterization of RhoGEF and RhoGAP substrate specificities.
- Analysis of RhoGEF and RhoGAP interactomes.
- Investigation of RhoGEF and RhoGAP localization within cells.
Main Results:
- RhoGEFs and RhoGAPs contextualize and spatiotemporally control Rho signaling.
- Proteins are autoinhibited for local regulation and form complexes for network coordination.
- RhoGAPs exhibit higher promiscuity than RhoGEFs, confining Rho activity gradients.
- A multi-RhoGEF complex downstream of GPCRs controls CDC42-RHOA crosstalk.
- Integrin adhesions segregate GEFs and GAPs to shape RAC1 activity zones in response to mechanical cues.
Conclusions:
- RhoGEF and RhoGAP networks provide positional information for signaling.
- Spatial segregation of regulators by adhesions controls cell motility dynamics.
- Systems analysis of Rho regulators reveals emergent organization principles of Rho signaling.
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