Dock3

DOCK3
Identifiers
Aliases	DOCK3, MOCA, PBP, Dock3, dedicator of cytokinesis 3, NEDIDHA
External IDs	OMIM: 603123 MGI: 2429763 HomoloGene: 21030 GeneCards: DOCK3
Gene location (Human)
Chr.	Chromosome 3 (human)[1]
End	51,384,198 bp[1]
Gene location (Mouse)
Chr.	Chromosome 9 (mouse)[2]
End	107,231,909 bp[2]
Gene ontology
Molecular function	• SH3 domain binding; • GO:0001948 protein binding; • guanyl-nucleotide exchange factor activity; • Rac guanyl-nucleotide exchange factor activity;
Cellular component	• cytoplasm; • cytosol;
Biological process	• small GTPase mediated signal transduction; • positive regulation of non-membrane spanning protein tyrosine kinase activity;
	Sources:Amigo / QuickGO
Orthologs
	1795
	208869
	ENSG00000088538
	ENSMUSG00000039716
	Q8IZD9
	Q8CIQ7
	NM_004947
	NM_153413
	NP_004938
	n/a
	Wikidata
View/Edit Human	View/Edit Mouse

Dock3 (Dedicator of cytokinesis 3), also known as MOCA (modifier of cell adhesion) and PBP (presenilin-binding protein), is a large (~180 kDa) protein involved in intracellular signalling 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.

Discovery

Dock3 was originally discovered in a screen for proteins that bind presenilin (a transmembrane protein which is mutated in early onset Alzheimer's disease).[6] Dock3 is specifically expressed in neurones (primarily in the cerebral cortex and hippocampus).

Structure and function

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-terminal SH3 domain, which in Dock180 binds ELMO (a family of adaptor proteins which mediate recruitment and efficient GEF activity of Dock180), and a C-terminal proline-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-SY5Y neuroblastoma 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]

gollark: Anyway, ABR has a connection open so I could instruct it to do things using the debug interface.

gollark: It's already too late.

gollark: You do realise that if I intended to "bee" you via that I could make ABR do it?

gollark: Oh, is it because I powered my laptop back on and it connected to IRC?

gollark: I didn't even hack your website much.

References

GRCh38: Ensembl release 89: ENSG00000088538 - Ensembl, May 2017
GRCm38: Ensembl release 89: ENSMUSG00000039716 - Ensembl, May 2017
"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
"Entrez Gene: DOCK3 dedicator of cytokinesis 3".
Kashiwa A, Yoshida H, Lee S, et al. (July 2000). "Isolation and characterization of novel presenilin binding protein". J. Neurochem. 75 (1): 109–16. doi:10.1046/j.1471-4159.2000.0750109.x. PMID 10854253.
Côté 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. PMID 12432077.
Hasegawa H, Kiyokawa E, Tanaka S, et al. (April 1996). "DOCK180, a major CRK-binding protein, alters cell morphology upon translocation to the cell membrane". Mol. Cell. Biol. 16 (4): 1770–76. doi:10.1128/mcb.16.4.1770. PMC 231163. PMID 8657152.
Hajdo-Milasinović A, Ellenbroek SI, van Es S, et al. (February 2007). "Rac1 and Rac3 have opposing functions in cell adhesion and differentiation of neuronal cells". J. Cell Sci. 120 (Pt 4): 555–66. doi:10.1242/jcs.03364. PMID 17244648.
Namekata K, Enokido Y, Iwasawa K, Kimura H (April 2004). "MOCA induces membrane spreading by activating Rac1". J. Biol. Chem. 279 (14): 14331–37. doi:10.1074/jbc.M311275200. PMID 14718541.
Chen Q, Chen TJ, Letourneau PC, et al. (January 2005). "Modifier of cell adhesion regulates N-cadherin-mediated cell-cell adhesion and neurite outgrowth". J. Neurosci. 25 (2): 281–90. doi:10.1523/JNEUROSCI.3692-04.2005. PMID 15647471.
Chen Q, Yoshida H, Schubert D, et al. (November 2001). "Presenilin Binding Protein Is Associated with Neurofibrillary Alterations in Alzheimer's Disease and Stimulates Tau Phosphorylation". Am. J. Pathol. 159 (5): 1567–602. doi:10.1016/S0002-9440(10)63005-2. PMC 1867048. PMID 11696419.
de Silva MG, Elliott K, Dahl HH, et al. (October 2003). "Disruption of a novel member of a sodium/hydrogen exchanger family and DOCK3 is associated with an attention deficit hyperactivity disorder-like phenotype". J. Med. Genet. 40 (10): 733–40. doi:10.1136/jmg.40.10.733. PMC 1735283. PMID 14569117.