DOCK2

DOCK2 (Dedicator of Cytokinesis 2) is a DOCK family guanine nucleotide exchange factor (GEF) that selectively activates Rac1/Rac2 GTPases. Unlike Dbl-domain GEFs, it employs a DOCK homology region 2 (DHR2) to catalyze GDP-GTP exchange on Rac. In lymphocytes (T/B cells, NK cells), DOCK2 mediates actin cytoskeleton rearrangement downstream of chemokine receptors (e.g., CXCR4, CCR7), enabling immune cell migration to lymphoid organs and antigen-driven immune synapse formation.
Pathogenic DOCK2 mutations cause autosomal recessive combined immunodeficiency (CID), marked by defective lymphocyte trafficking and recurrent infections. Dysregulated DOCK2 activity is also linked to autoimmune diseases (e.g., rheumatoid arthritis) via excessive immune cell infiltration, and hematological malignancies (e.g., acute myeloid leukemia) through promoting cancer cell migration/metastasis. Preclinical inhibitors targeting DOCK2’s DHR2 domain are under development for treating autoimmune disorders and metastatic cancers.