DOCK family proteins: key players in immune surveillance mechanisms

Dedicator of cytokinesis (DOCK) proteins constitute a family of evolutionarily conserved guanine nucleotide exchange factors (GEFs) for the Rho family of GTPases. Although DOCK family proteins do not contain the Dbl homology domain typically found in other GEFs, they mediate the GTP-GDP exchange reaction through the DOCK homology region-2 (DHR-2) domain. In mammals, this family consists of 11 members, each of which has unique functions depending on the expression pattern and the substrate specificity. For example, DOCK2 is a Rac activator critical for migration and activation of leukocytes, whereas DOCK8 is a Cdc42-specific GEF that regulates interstitial migration of dendritic cells. Identification of DOCK2 and DOCK8 as causative genes for severe combined immunodeficiency syndromes in humans has highlighted their roles in immune surveillance. In addition, the recent discovery of a naturally occurring DOCK2-inhibitory metabolite has uncovered an unexpected mechanism of tissue-specific immune evasion. On the other hand, GEF-independent functions have been shown for DOCK8 in antigen-induced IL-31 production in helper T cells. This review summarizes multifaced functions of DOCK family proteins in the immune system.