Integrated Studies on the Biological Functions and Regulatory Mechanisms of Dedicator of Cytokinesis Family Proteins—Secondary Publication

Abstract

Small guanosine triphosphatases act as molecular switches in signaling pathways by alternating between an inactive guanosine diphosphate (GDP)–bound state and an active guanosine triphosphate (GTP)–bound state. Upon activation, they interact with various effector molecules to regulate a wide range of cellular processes. This activation is triggered by external stimuli and is mediated by guanine nucleotide exchange factors (GEFs). GEFs are classified into two major types: Dbl homology (DH)–domain-containing proteins (DH-type GEFs) and dedicator of cytokinesis (DOCK) proteins (DOCK-type GEFs). Traditionally, DH-type GEFs were thought to represent the universal GEFs in eukaryotic systems. However, since we first demonstrated the crucial role of DOCK2 in lymphocyte migration, accumulating evidence has highlighted the importance of DOCK family proteins in diverse biological responses. These proteins share two evolutionarily conserved domains: DOCK homology region-1 (DHR-1) and DHR-2. The DHR-1 domain mediates phospholipid binding, which governs the intracellular localization of DOCK proteins, whereas the DHR-2 domain functions as the catalytic site for GDP–GTP exchange reaction on Rac or Cdc42. In mammals, the DOCK family comprises 11 members. In this review, I summarize the biological functions and regulatory mechanisms of DOCK proteins, with a particular emphasis on DOCK2 and DOCK8.