Dedicator of cytokinesis protein 3

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 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.

DOCK3
Identifiers
Aliases	DOCK3, MOCA, PBP, Dock3, dedicator of cytokinesis 3, NEDIDHA
External IDs	OMIM: 603123; MGI: 2429763; HomoloGene: 21030; GeneCards: DOCK3; OMA:DOCK3 - orthologs
Gene location (Human) Chr. Chromosome 3 (human)[1] Band 3p21.2 Start 50,674,927 bp[1] End 51,384,198 bp[1]
Gene location (Mouse) Chr. Chromosome 9 (mouse)[2] Band 9|9 F1 Start 106,770,024 bp[2] End 107,109,108 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in frontal pole Brodmann area 10 paraflocculus of cerebellum middle frontal gyrus postcentral gyrus Brodmann area 46 orbitofrontal cortex superior frontal gyrus cerebellar vermis dorsolateral prefrontal cortex Top expressed in dentate gyrus of hippocampal formation granule cell superior frontal gyrus primary visual cortex piriform cortex primary motor cortex olfactory tubercle zygote prefrontal cortex cerebellar cortex temporal lobe More reference expression data BioGPS n/a
Gene ontology Molecular function SH3 domain binding protein binding 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 Species Human Mouse Entrez 1795 208869 Ensembl ENSG00000088538 ENSMUSG00000039716 UniProt Q8IZD9 Q8CIQ7 RefSeq (mRNA) NM_004947 NM_153413 RefSeq (protein) NP_004938 n/a Location (UCSC) Chr 3: 50.67 – 51.38 Mb Chr 9: 106.77 – 107.11 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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 neurons (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]

References

1. GRCh38: Ensembl release 89: ENSG00000088538 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000039716 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: DOCK3 dedicator of cytokinesis 3".
6. 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. S2CID 24838995.
7. 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. S2CID 14669715.
8. 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.
9. 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.
10. 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.
11. 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. PMC 6725471. PMID 15647471.
12. 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.
13. 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.

Further reading

• Côté JF, Vuori K (2007). "GEF what? Dock180 and related proteins help Rac to polarize cells in new ways". Trends Cell Biol. 17 (8): 383–93. doi:10.1016/j.tcb.2007.05.001. PMC 2887429. PMID 17765544.
• Meller N, Merlot S, Guda C (2005). "CZH proteins: a new family of Rho-GEFs". J. Cell Sci. 118 (Pt 21): 4937–46. doi:10.1242/jcs.02671. PMID 16254241. S2CID 3075895.
• 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. ISBN 9780121828110. PMID 16472648.
• Chen Q, Kimura H, Schubert D (2002). "A novel mechanism for the regulation of amyloid precursor protein metabolism". J. Cell Biol. 158 (1): 79–89. doi:10.1083/jcb.200110151. PMC 2173011. PMID 12093789.
• Brion JP, Anderton BH, Authelet M, et al. (2001). "Neurofibrillary tangles and tau phosphorylation" (PDF). Biochem. Soc. Symp. 67 (67): 81–88. doi:10.1042/bss0670081. PMID 11447842.
• Kim JM, Lee KH, Jeon YJ, et al. (2007). "Identification of genes related to Parkinson's disease using expressed sequence tags". DNA Res. 13 (6): 275–86. doi:10.1093/dnares/dsl016. PMID 17213182.