Dedicator of cytokinesis protein 3 (Dock3), also known asMOCA (modifierofcelladhesion) andPBP (presenilin-bindingprotein), is a large (~180 kDa)protein encoded in the human by theDOCK3 gene, involved inintracellularsignalling networks.[5] It is a member of the DOCK-B subfamily of theDOCK family ofguanine nucleotide exchange factors (GEFs) which function as activators ofsmall G-proteins. Dock3 specifically activates the small G proteinRac.
Dock3 is part of a large class of proteins (GEFs) which contribute to cellular signalling events by activating small G proteins. In their resting state G proteins are bound toGuanosine diphosphate (GDP) and their activation requires the dissociation of GDP and binding ofguanosine triphosphate (GTP). GEFs activate G proteins by promoting this nucleotide exchange.
Dock3 exhibits the samedomain arrangement asDock180 (a member of the DOCK-A subfamily and the archetypal member of the DOCK family) and these proteins share a considerable (40%) degree ofsequence similarity.[7]
Since Dock3 shares the same domain arrangement as Dock180 it is predicted to have a similar array of binding partners, although this has yet to be demonstrated. It contains anN-terminalSH3 domain, which in Dock180 bindsELMO (a family ofadaptor proteins which mediate recruitment and efficient GEF activity of Dock180), and aC-terminalproline-rich region which, in Dock180, binds the adaptor proteinCRK.[7][8]
Dock3 GEF activity is directed specifically atRac1. Dock3 has not been shown to interact withRac3, another Rac protein which is expressed in neuronal cells, and this may be because Rac3 is primarily located in the perinuclear region. In fact, Rac1 and Rac3 appear to have distinct and antagonistic roles in these cells.[9] Dock3-mediated Rac1 activation promotes reorganisation of thecytoskeleton inSH-SY5Yneuroblastoma cells and primarycortical neurones as well asmorphological changes infibroblasts.[10] It has also been shown to regulateneurite outgrowth andcell-cell adhesion inB103 andPC12 cells.[11]
The first indication that Dock3 might be involved in neurological disorders came when Dock3 was shown to bind to presenilin, a transmembrane enzyme involved in the generation ofbeta amyloid (Aβ),[6] accumulation of which is an important step in the development of Alzheimer's disease. Dock3 has been shown to undergo redistribution and association withneurofibrillary tangles in brain samples from patients with Alzheimer's disease.[12] A mutation in Dock3 was also identified in a family displaying aphenotype resemblingattention-deficit hyperactivity disorder (ADHD).[13]
^abCôté JF, Vuori K (December 2002). "Identification of an evolutionarily conserved superfamily of DOCK180-related proteins with guanine nucleotide exchange activity".J. Cell Sci.115 (Pt 24):4901–13.doi:10.1242/jcs.00219.PMID12432077.S2CID14669715.
Côté JF, Vuori K (2006). "In Vitro Guanine Nucleotide Exchange Activity of DHR-2/DOCKER/CZH2 Domains".Regulators and Effectors of Small GTPases: Rho Family. Methods in Enzymology. Vol. 406. pp. 41–57.doi:10.1016/S0076-6879(06)06004-6.ISBN9780121828110.PMID16472648.
