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.
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Etienne-Manneville, S. & Hall, A. Rho GTPases in cell biology. Nature 420, 629–635 (2002)
Gumienny, T. L. et al. CED-12/ELMO, a novel member of the CrkII/Dock180/Rac pathway, is required for phagocytosis and cell migration. Cell 107, 27–41 (2001)
Zhou, Z., Caron, E., Hartwieg, E., Hall, A. & Horvitz, R. The C. elegans PH domain protein CED-12 regulates cytoskeletal reorganization via a Rho/Rac GTPase signaling pathway. Dev. Cell 1, 477–489 (2001)
Wu, Y. C., Tsai, M. C., Cheng, L. C., Chou, C. J. & Weng, N. Y. C. elegans CED-12 acts in the conserved CrkII/Dock180/Rac pathway to control cell migration and cell corpse engulfment. Dev. Cell 1, 491–502 (2001)
Brugnera, E. et al. Unconventional Rac-GEF activity is mediated through the Dock180–Elmo complex. Nature Cell Biol. 4, 574–582 (2002)
Cote, J. F. & Vuori, K. Identification of an evolutionarily conserved superfamily of Dock180-related proteins with guanine nucleotide exchange activity. J. Cell Sci. 115, 4901–4913 (2002)
Gauthier-Rouviere, C. et al. RhoG GTPase controls a pathway that independently activates Rac1 and Cdc42Hs. Mol. Biol. Cell 9, 1379–1394 (1998)
Blangy, A., Schmidt, V. S., Debant, A., Gauthier-Rouviere, C. & Fort, P. TrioGEF1 controls Rac- and Cdc42-dependent cell structures through the direct activation of RhoG. J. Cell Sci. 113, 729–739 (2000)
Katoh, H. et al. Small GTPase RhoG is a key regulator for neurite outgrowth in PC12 cells. Mol. Cell Biol. 20, 7378–7387 (2000)
Estrach, S. et al. The human Rho-GEF Trio and its target GTPase RhoG are involved in the NGF pathway, leading to neurite outgrowth. Curr. Biol. 12, 307–312 (2002)
May, V., Schiller, M. R., Eipper, B. A. & Mains, R. E. Kalirin Dbl-homology guanine nucleotide exchange factor 1 domain initiates new axon outgrowths via RhoG-mediated mechanisms. J. Neurosci. 22, 6980–6990 (2002)
Vigorito, E. et al. RhoG regulates gene expression and the actin cytoskeleton in lymphocytes. Oncogene 22, 330–342 (2003)
Manser, E., Leung, T., Salihuddin, H., Zhao, Z. S. & Lim, L. A brain serine/threonine protein kinase activated by Cdc42 and Rac1. Nature 367, 40–46 (1994)
Reid, T. et al. Rhotekin, a new putative target for Rho bearing homology to a serine/threonone kinase PKN, and Rhophilin in the Rho-binding domain. J. Biol. Chem. 271, 13556–13560 (1996)
Hasegawa, H. et al. Dock180, a major CRK-binding protein, alters cell morphology upon translocation to the cell membrane. Mol. Cell. Biol. 16, 1770–1776 (1996)
Kiyokawa, E. et al. Activation of Rac1 by a Crk SH3-binding protein, DOCK180. Genes Dev. 12, 3331–3336 (1998)
Kiyokawa, E. et al. Evidence that Dock180 up-regulates signals from the CrkII-p130Cas complex. J. Biol. Chem. 273, 24479–24484 (1998)
Albert, M. L., Kim, J. & Birge, R. B. αvβ5 integrin recruits the CrkII–Dock180–Rac1 complex for phagocytosis of apoptotic cells. Nature Cell Biol. 2, 899–905 (2000)
Gu, J., Sumida, Y., Sanzen, N. & Sekiguchi, K. Laminin-10/11 and fibronectin differentially regulates integrin-dependent Rho and Rac activation via p130Cas–CrkII–Dock180 pathway. J. Biol. Chem. 276, 27090–27097 (2001)
Clark, E. A., King, W. G., Brugge, J. S., Symons, M. & Hynes, R. O. Integrin-mediated signals regulated by members of the Rho family of GTPases. J. Cell Biol. 142, 573–586 (1998)
Price, L. S., Leng, J., Schwartz, M. A. & Bokoch, G. M. Activation of Rac and Cdc42 by integrins mediates cell spreading. Mol. Biol. Cell 9, 1863–1871 (1998)
Lundquist, E. A. et al. Three C. elegans Rac proteins and several alternative Rac regulators control axon guidance, cell migration and apoptotic cell phagocytosis. Development 128, 4475–4488 (2001)
Wu, Y. C., Cheng, T. W., Lee, M. C. & Weng, N. Y. Distinct Rac activation pathways control Caenorhabditis elegans cell migration and axon outgrowth. Dev. Biol. 250, 145–155 (2002)
Steven, R. et al. UNC-73 activates the Rac GTPase and is required for cell and growth cone migrations in C. elegans. Cell 92, 785–795 (1998)
Katoh, H., Harada, A., Mori, K. & Negishi, M. Socius is a novel Rnd GTPase-interacting protein involved in disassembly of actin stress fibers. Mol. Cell. Biol. 22, 2952–2964 (2002)
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.
The authors declare that they have no competing financial interests.
About this article
Cite this article
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
Cooperative recruitment of Arl4A and Pak1 to the plasma membrane contributes to sustained Pak1 activation for cell migration
Journal of Cell Science (2020)
Frontiers in Physiology (2020)
RhoG/Rac1 signaling pathway involved in migration and invasion of salivary adenoid cystic carcinoma cells
Oral Diseases (2020)
Prenatal diagnosis of concomitant distal 5q duplication and terminal 10q deletion in a fetus with intrauterine growth restriction, congenital diaphragmatic hernia and congenital heart defects
Taiwanese Journal of Obstetrics and Gynecology (2020)