Dock3

DOCK3
Identifiers
Aliases DOCK3, MOCA, PBP, Dock3, dedicator of cytokinesis 3
External IDs MGI: 2429763 HomoloGene: 21030 GeneCards: DOCK3
Genetically Related Diseases
melanoma[1]
Orthologs
Species Human Mouse
Entrez

1795

208869

Ensembl

ENSG00000088538

ENSMUSG00000039716

UniProt

Q8IZD9

Q8CIQ7

RefSeq (mRNA)

NM_004947

NM_153413

RefSeq (protein)

NP_004938.1

n/a

Location (UCSC) Chr 3: 50.68 – 51.38 Mb Chr 9: 106.89 – 107.23 Mb
PubMed search [2] [3]
Wikidata
View/Edit HumanView/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.[4] 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).[5] 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.[6]

Regulation of Dock3 activity

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.[6][7]

Signalling downstream of Dock3

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.[8] 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.[9] It has also been shown to regulate neurite outgrowth and cell-cell adhesion in B103 and PC12 cells.[10]

Dock3 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),[5] 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 Alzheimers patients.[11] A mutation in Dock3 was also identified in a family displaying a phenotype resembling attention-deficit hyperactivity disorder (ADHD).[12]

References

  1. ↑ "Diseases that are genetically associated with DOCK3 view/edit references on wikidata".
  2. ↑ "Human PubMed Reference:".
  3. ↑ "Mouse PubMed Reference:".
  4. ↑ "Entrez Gene: DOCK3 dedicator of cytokinesis 3".
  5. 1 2 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.
  6. 1 2 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.
  7. ↑ 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. PMC 231163Freely accessible. PMID 8657152.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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 1867048Freely accessible. PMID 11696419.
  12. ↑ 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 1735283Freely accessible. PMID 14569117.

Further reading

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