Dedicator of cytokinesis protein 3 explained

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.^[1] 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).^[2] 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.^[3]

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.^{[3] [4]}

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.^[5] 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.^[6] It has also been shown to regulate neurite outgrowth and cell-cell adhesion in B103 and PC12 cells.^[7]

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),^[2] 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.^[8] A mutation in Dock3 was also identified in a family displaying a phenotype resembling attention-deficit hyperactivity disorder (ADHD).^[9]

Further reading

• Côté JF, Vuori K . GEF what? Dock180 and related proteins help Rac to polarize cells in new ways. Trends Cell Biol. . 17 . 8. 383–93. 2007 . 17765544 . 10.1016/j.tcb.2007.05.001 . 2887429.
• Meller N, Merlot S, Guda C. CZH proteins: a new family of Rho-GEFs. J. Cell Sci. . 118 . Pt 21. 4937–46. 2005 . 16254241 . 10.1242/jcs.02671. 3075895.
• Book: Côté JF, Vuori K . In Vitro Guanine Nucleotide Exchange Activity of DHR-2/DOCKER/CZH2 Domains . Regulators and Effectors of Small GTPases: Rho Family. Methods in Enzymology. 406 . 41–57. 2006 . 16472648 . 10.1016/S0076-6879(06)06004-6. 9780121828110.
• Chen Q, Kimura H, Schubert D . A novel mechanism for the regulation of amyloid precursor protein metabolism . J. Cell Biol. . 158 . 1 . 79–89 . 2002 . 12093789 . 10.1083/jcb.200110151 . 2173011.
• Brion JP, Anderton BH, Authelet M . Neurofibrillary tangles and tau phosphorylation . Biochem. Soc. Symp. . 67 . 67. 81–88 . 2001 . 11447842 . 10.1042/bss0670081. etal.
• Kim JM, Lee KH, Jeon YJ . Identification of genes related to Parkinson's disease using expressed sequence tags. DNA Res. . 13 . 6. 275–86 . 2007 . 17213182 . 10.1093/dnares/dsl016. etal. free .

Notes and References

1. Web site: Entrez Gene: DOCK3 dedicator of cytokinesis 3.
2. Kashiwa A, Yoshida H, Lee S . Isolation and characterization of novel presenilin binding protein . J. Neurochem. . 75 . 1 . 109–16 . July 2000 . 10854253 . 10.1046/j.1471-4159.2000.0750109.x. 24838995 . etal. free .
3. Côté JF, Vuori K . Identification of an evolutionarily conserved superfamily of DOCK180-related proteins with guanine nucleotide exchange activity . J. Cell Sci. . 115 . Pt 24 . 4901–13 . December 2002 . 12432077 . 10.1242/jcs.00219. 14669715 .
4. Hasegawa H, Kiyokawa E, Tanaka S . DOCK180, a major CRK-binding protein, alters cell morphology upon translocation to the cell membrane . Mol. Cell. Biol. . 16 . 4 . 1770–76 . April 1996. 8657152 . 10.1128/mcb.16.4.1770. 231163 . etal.
5. Hajdo-Milasinović A, Ellenbroek SI, van Es S . Rac1 and Rac3 have opposing functions in cell adhesion and differentiation of neuronal cells . J. Cell Sci. . 120 . Pt 4 . 555–66 . February 2007. 17244648 . 10.1242/jcs.03364. etal. free .
6. Namekata K, Enokido Y, Iwasawa K, Kimura H. MOCA induces membrane spreading by activating Rac1. J. Biol. Chem. . 279 . 14 . 14331–37 . April 2004 . 14718541 . 10.1074/jbc.M311275200. free .
7. Chen Q, Chen TJ, Letourneau PC. Modifier of cell adhesion regulates N-cadherin-mediated cell-cell adhesion and neurite outgrowth. J. Neurosci. . 25 . 2 . 281–90 . January 2005 . 15647471 . 10.1523/JNEUROSCI.3692-04.2005. 6725471. etal. free .
8. Chen Q, Yoshida H, Schubert D. Presenilin Binding Protein Is Associated with Neurofibrillary Alterations in Alzheimer's Disease and Stimulates Tau Phosphorylation. Am. J. Pathol. . 159 . 5 . 1567–602 . November 2001 . 11696419 . 10.1016/S0002-9440(10)63005-2. 1867048 . etal.
9. de Silva MG, Elliott K, Dahl HH. 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 . October 2003 . 14569117 . 10.1136/jmg.40.10.733. 1735283 . etal.