ABSTRACT
Worms and Flies ......................................................................................... 174 13.5 ELMO: Additional Component of Evolutionarily Conserved
Crk/DOCK180/Rac Pathway ...................................................................... 175 13.6 Rho GTPases and Their Regulators ........................................................... 175 13.7 Rac Activation by Crk/ELMO/DOCK180 Complex .................................. 176 13.8 Identification of DOCK180 Superfamily of Proteins ................................. 177 13.9 Identification of DHR-2 Domain of DOCK180 as Novel GEF for Rac ...... 181 13.10 DOCK180-Related Proteins Constitute Novel Superfamily of GEFs
with Diverse Biological Functions .............................................................. 183 Acknowledgments .................................................................................................. 186 References .............................................................................................................. 186
Mammalian DOCK180 protein and its orthologues Myoblast City (MBC) and ced-5 in Drosophila and Caenorhabditis elegans, respectively, have been known for some time to function as critical regulators of the small GTPase Rac during several fundamentally important biological processes, such as cell motility and phagocytosis. The mechanism by which DOCK180 and its orthologues regulate Rac has remained elusive until recently. Our studies to uncover this fundamental mechanism produced several unexpected novel discoveries. Among them is the identification of a novel protein domain termed DHR-2 within the DOCK180 protein that interacts with and activates GTPases. Additionally, we identified several novel homologues of DOCK180 that possess this domain, and found that many of them directly bind to and exchange GDP for GTP both in vitro and in vivo on Rho GTPases. Thus, our studies uncovered a novel signaling module, and also resulted in a discovery of an
evolutionarily conserved DOCK180-related superfamily of exchange factors, opening new opportunities in biological research. Our studies, as well as those of numerous colleagues that led to these findings are discussed in this chapter.
