Immune regulatory functions of DOCK family proteins in health and disease

• DOCK proteins constitute a family of evolutionarily conserved GEFs for Rho GTPases.
• DOCK2 regulates migration and activation of leukocytes through Rac activation.
• Mutations of DOCK8 cause a combined immunodeficiency syndrome in humans.
• DOCK8 regulates interstitial DC migration by spatially controlling Cdc42 activity.

DOCK proteins constitute a family of evolutionarily conserved guanine nucleotide exchange factors (GEFs) for Rho family of GTPases. Although DOCK family proteins do not contain the Dbl homology domain typically found in GEFs, they mediate the GTP–GDP exchange reaction through DHR-2 domain. Accumulating evidence indicates that the DOCK proteins act as major GEFs in varied biological settings. For example, DOCK2, which is predominantly expressed in hematopoietic cells, regulates migration and activation of leukocytes through Rac activation. On the other hand, it was recently reported that mutations of DOCK8, another member of the DOCK family proteins, cause a combined immunodeficiency syndrome in humans. This article reviews the structure, functions and signaling of DOCK2 and DOCK8, especially focusing on their roles in immune responses.