A Docker Instead of a Dbl

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Overexpression of Dock180 can stimulate nucleotide exchange on the guanosine triphosphatase (GTPase) Rac, promoting such cellular responses as membrane ruffling and phagocytosis, and this effect is enhanced if two other proteins are also expressed, ELMO1 and the adaptor CrkII. These data suggested that Dock180 is a guanine exchange factor (GEF) for Rac; however, Dock180 lacks the Dbl homology (DH) domain responsible for GEF activity in all other known GEFs. Brugnera et al. investigated in vitro and in transfected cells Dock180's GEF activity and identified a new domain, which they call Docker, that bound to Rac and promoted GTP loading. The docker domain is conserved in other members of the mammalian Dock180 family and in a protein encoded by a yeast gene implicated in the control of filamentous growth. These domains from Dock2 and the protein encoded in the yeast gene also interacted with Rac in vitro. Mutations in the Docker domain or the ELMO binding domain prevented the stimulation of membrane ruffles or particle engulfment in cells transfected with the mutated Dock180 and ELMO1. Coprecipitation of Dock180 and Rac in transfected cells was enhanced if ELMO was also transfected into the cells, suggesting that ELMO1 may promote the Dock180-Rac interaction. However, the mechanism by which these proteins work together to regulate Rac activity remains unknown. E. Brugnera, L. Haney, C. Grimsley, M. Lu, S. F. Walk, A.-C. Tosello-Trampont, I. G. Macara, H. Madhani, G. R. Fink, K. S. Ravichandran, Unconventional Rac-GEF activity is mediated through the Dock180-ELMO complex. Nat. Cell Biol. 4 , 574-582 (2002). [Online Journal]