Fig. 3.

GEF-independent or GEF-dependent immune regulatory functions of DOCK8. DOCK8 is a Cdc42-specific GEF that links Cdc42 activation to actomyosin dynamics through the association with LRAP35a. This signaling cascade is required for mDCs to pass through the narrow gaps of three-dimensional (3D) fibrillar networks and transmigrate through the subcapsular sinus floor of the LNs. On the other hand, IL-31 is a major pruritogen associated with AD. DOCK8 negatively regulates antigen-induced IL-31 production by helper T cells. This function does not require the Cdc42 GEF activity, but is mediated by formation of trimolecular complex composed of mammalian ste-20 like kinase 1 (MST1) and endothelial PAS domain 1 (EPAS1). EPAS1 is a master regulator for IL-31 induction, thereby serving as a therapeutic target for controlling AD-associated itch.