Elmo1 and Elmo2 are highly homologous cytoplasmic adaptor proteins that interact 
with Dock family guanine nucleotide exchange factors to promote activation of 
the small GTPase Rac. In T lymphocytes, Dock2 is essential for CCR7- and 
CXCR4-dependent Rac activation and chemotaxis, but the role of Elmo proteins in 
regulating Dock2 function in primary T cells is not known. In this article, we 
show that endogenous Elmo1, but not Elmo2, interacts constitutively with Dock2 
in mouse and human primary T cells. CD4(+) T cells from Elmo1(-/-) mice were 
profoundly impaired in polarization, Rac activation, and chemotaxis in response 
to CCR7 and CXCR4 stimulation. Transfection of full-length Elmo1, but not Elmo2 
or a Dock2-binding mutant of Elmo1, rescued defective migration of Elmo1(-/-) T 
cells. Interestingly, Dock2 protein levels were reduced by 4-fold in Elmo1(-/-) 
lymphocytes despite normal levels of Dock2 mRNA. Dock2 polyubiquitination was 
increased in Elmo1(-/-) T cells, and treatment with proteasome inhibitors 
partially restored Dock2 levels in Elmo1(-/-) T cells. Finally, we show that 
Dock2 is directly ubiquitinated in CD4(+) T cells and that Elmo1 expression in 
heterologous cells inhibits ubiquitination of Dock2. Taken together, these 
findings reveal a previously unknown, nonredundant role for Elmo1 in controlling 
Dock2 levels and Dock2-dependent T cell migration in primary lymphocytes. 
Inhibition of Dock2 has therapeutic potential as a means to control recruitment 
of pathogenic lymphocytes in diseased tissues. This work provides valuable 
insights into the molecular regulation of Dock2 by Elmo1 that can be used to 
design improved inhibitors that target the Elmo-Dock-Rac signaling complex.