RhoG activates Rac1 by direct interaction with the Dock180-binding protein Elmo

Abstract

The small GTPase Rac has a central role in regulating the actin cytoskeleton during cell migration and axon guidance1. Elmo has been identified as an upstream regulator of Rac1 that binds to and functionally cooperates with Dock180 (refs 2–4). Dock180 does not contain a conventional catalytic domain for guanine nucleotide exchange on Rac, but possesses a domain that directly binds to and specifically activates Rac1 (refs 5, 6). The small GTPase RhoG mediates several cellular morphological processes, such as neurite outgrowth in neuronal cells, through a signalling cascade that activates Rac1 (refs 7–12); however, the downstream target of RhoG and the mechanism by which RhoG regulates Rac1 activity remain unclear. Here we show that RhoG interacts directly with Elmo in a GTP-dependent manner and forms a ternary complex with Dock180 to induce activation of Rac1. The RhoG–Elmo–Dock180 pathway is required for activation of Rac1 and cell spreading mediated by integrin, as well as for neurite outgrowth induced by nerve growth factor. We conclude that RhoG activates Rac1 through Elmo and Dock180 to control cell morphology.

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Figure 1: Elmo binds directly to RhoG in a GTP-dependent manner.
Figure 2: RhoG activates Rac1 through Elmo and Dock180.
Figure 3: Mutants of Elmo and Dock180 suppress Rac1 activation and cell spreading mediated by integrin.
Figure 4: Mutants of Elmo and Dock180 suppress NGF- and RhoG-induced neurite outgrowth in PC12 cells.

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Acknowledgements

We thank M. Matsuda for the Dock180 expression plasmid. This work was supported in part by Grants-in-aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan and a grant from the Takeda Science Foundation.

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Correspondence to Hironori Katoh.

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Katoh, H., Negishi, M. RhoG activates Rac1 by direct interaction with the Dock180-binding protein Elmo. Nature 424, 461–464 (2003). https://doi.org/10.1038/nature01817

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