Dedicator of cytokinesis protein 3 (Dock3), also known as MOCA (modifier of cell adhesion) and PBP (presenilin-binding protein), is a large (~180 kDa)
protein encoded in the human by the DOCK3 gene, involved in
intracellularsignalling networks.[5] It is a member of the DOCK-B subfamily of the
DOCK family of
guanine nucleotide exchange factors (GEFs) which function as activators of
small G-proteins. Dock3 specifically activates the small G protein
Rac.
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 to
Guanosine diphosphate (GDP) and their activation requires the dissociation of GDP and binding of
guanosine triphosphate (GTP). GEFs activate G proteins by promoting this nucleotide exchange.
Dock3 exhibits the same
domain arrangement as
Dock180 (a member of the DOCK-A subfamily and the archetypal member of the DOCK family) and these proteins share a considerable (40%) degree of
sequence similarity.[7]
Regulation
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 an
N-terminalSH3 domain, which in Dock180 binds
ELMO (a family of
adaptor proteins which mediate recruitment and efficient GEF activity of Dock180), and a
C-terminalproline-rich region which, in Dock180, binds the adaptor protein
CRK.[7][8]
Downstream signalling
Dock3 GEF activity is directed specifically at
Rac1. Dock3 has not been shown to interact with
Rac3, 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 the
cytoskeleton in
SH-SY5Yneuroblastoma cells and primary
cortical neurones as well as
morphological changes in
fibroblasts.[10] It has also been shown to regulate
neurite outgrowth and
cell-cell adhesion in
B103 and
PC12 cells.[11]
In neurological disorders
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 of
beta 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 with
neurofibrillary tangles in brain samples from patients with Alzheimer's disease.[12] A mutation in Dock3 was also identified in a family displaying a
phenotype resembling
attention-deficit hyperactivity disorder (ADHD).[13]
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.