Cell migration is essential throughout embryonic and adult life. In numerous 
cell systems, the small GTPase Rac is required for lamellipodia formation at the 
leading edge and movement ability. However, the molecular mechanisms leading to 
Rac activation during migration are still unclear. Recently, a mammalian 
superfamily of proteins related to the prototype member Dock180 has been 
identified with homologues in Drosophila and Caenorhabditis elegans. Here, we 
addressed the role of Dock180 and ELMO1 proteins, which function as a complex to 
mediate Rac activation, in mammalian cell migration. Using mutants of Dock180 
and ELMO1 in a Transwell assay as well as transgenic rescue of a C. elegans 
mutant lacking CED-5 (Dock180 homologue), we identified specific regions of 
Dock180 and ELMO1 required for migration in vitro and in a whole animal model. 
In both systems, the Dock180.ELMO1 complex formation and the ability to activate 
Rac were required. We also found that ELMO1 regulated multiple Dock180 
superfamily members to promote migration. Interestingly, deletion mutants of 
ELMO1 missing their first 531 or first 330 amino acids that can still bind and 
cooperate with Dock180 in Rac activation failed to promote migration, which 
correlated with the inability to localize to lamellipodia. This finding suggests 
that Rac activation by the ELMO.Dock180 complex at discrete intracellular 
locations mediated by the N-terminal 330 amino acids of ELMO1 rather than 
generalized Rac activation plays a role in cell migration.