Dock2

DOCK2
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
Aliases DOCK2, IMD40, Dock2, dedicator of cytokinesis 2
External IDs MGI: 2149010 HomoloGene: 37984 GeneCards: DOCK2
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez

1794

94176

Ensembl

ENSG00000134516

ENSMUSG00000020143

UniProt

Q92608

Q8C3J5

RefSeq (mRNA)

NM_004946

NM_033374

RefSeq (protein)

NP_004937.1

NP_203538.2

Location (UCSC) Chr 5: 169.64 – 170.08 Mb Chr 11: 34.23 – 34.78 Mb
PubMed search [1] [2]
Wikidata
View/Edit HumanView/Edit Mouse

Dock2 (Dedicator of cytokinesis 2), also known as DOCK2, is a large (~180 kDa) protein involved in intracellular signalling networks.[3] It is a member of the DOCK-A subfamily of the DOCK family of guanine nucleotide exchange factors (GEFs) which function as activators of small G proteins. Dock2 specifically activates isoforms of the small G protein Rac.

Discovery

Dock2 was first characterised as one of a number of proteins which shared high sequence similarity with the previously described protein Dock180, the archetypal member of the DOCK family. Whereas Dock180 expression is near ubiquitous in mammals, Dock2 appears to be expressed specifically in leukocytes and is considered to be the principal DOCK family member in these cells.[4]

Structure and Function

Dock2 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.

Dock2 and other DOCK family proteins differ from other GEFs in that they do not possess the canonical structure of tandem DH-PH domains known to elicit nucleotide exchange. Instead they possess a DHR2 domain which mediates Rac activation by stabilising it in its nucleotide-free state.[5] They also contain a DHR1 domain which binds phospholipids and is required for the interaction between Dock2 and the plasma membrane.[6] As with other members of the DOCK-A and DOCK-B subfamilies, Dock2 contains an N-terminal SH3 domain which is involved in binding to ELMO proteins (see below).[7] Dock180 contains a C-terminal proline rich region which mediates binding to Crk, however, Dock2 lacks this feature[4] despite the fact that it is able to bind the Crk-like protein CrkL.[8]

Regulation of Dock2 activity

Efficient Dock180 GEF activity in a cellular context is known to require the formation of a complex between Dock180 and its cognate adaptor proteins, which assist its translocation to the plasma mambrane and binding to Rac.[9][10] Similarly, Dock2 has been shown to form a complex with the well described DOCK-binding protein ELMO1 and this interaction is required for Dock2-mediated Rac activation in lymphocyte cell lines.[7] ELMO proteins contain a C-terminal proline-rich region which binds to the N-terminal SH3 domain of DOCK proteins and mediates their recruitment to sites of high Rac availability (primarily the plasma membrane).[10] ELMO proteins also contain a PH domain which appears to induce conformational changes in DOCK and thus allow binding to Rac.[11]

Signalling downstream of Dock2

Like other DOCK-A and DOCK-B subfamily proteins Dock2 GEF activity is specific for Rac. Leukocytes express both Rac1 and Rac2 and Dock2 has been shown to bind and promote nucleotide exchange on both of these isoforms.[4] Rac isoforms regulate a multitude of processes in leukocytes and studies so far have shown that Dock2-dependent Rac activation regulates the neutrophil NADPH oxidase[6] and is also important for chemotaxis in neutrophils,[6][12] lymphocytes[13] and plasmacytoid dendritic cells.[14] Dock2-dependent NADPH oxidase activation was reported in response to the soluble agonist fMLP, which acts via G protein-coupled receptors in neutrophils.[6] Dock2-dependent chemotaxis has been reported in response to the chemokines CXCL12/SDF-1 in T lymphocytes, CXCL13/BLC in B lymphocytes and CCL19/ELC in thymocytes (immature lymphocytes) emigrating from the thymus[13] as well as CCL21/SLC in ex vivo plasmacytoid dendritic cells.[14] In neutrophil chemotaxis Dock2 signals downstream of the C5a and CXCL8/IL-8 receptors.[6][12] Additional receptors which signal through Dock2 include the T cell receptor/TCR[8] and EDG1, a sphingosine-1-phosphate (S1P) receptor.[15] Interestingly, the HIV-1 protein Nef is able to constitutively activate Dock2 in T lymphocytes which disrups chemotaxis and immunological synapse formation thereby inhibiting the antiviral immune response.[16]

Interactions

Dock2 has been shown to interact with CRKL.[17]

References

  1. ↑ "Human PubMed Reference:".
  2. ↑ "Mouse PubMed Reference:".
  3. ↑ "Entrez Gene: DOCK2 dedicator of cytokinesis 2".
  4. 1 2 3 Nishihara H, Kobayashi S, Hashimoto Y, et al. (November 1999). "Non-adherent cell-specific expression of DOCK2, a member of the human CDM-family proteins". Biochim. Biophys. Acta. 1452 (2): 179–87. doi:10.1016/S0167-4889(99)00133-0. PMID 10559471.
  5. ↑ 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.
  6. 1 2 3 4 5 Kunisaki Y, Nishikimi A, Tanaka Y, et al. (August 2006). "DOCK2 is a Rac activator that regulates motility and polarity during neutrophil chemotaxis". J. Cell Biol. 174 (5): 647–52. doi:10.1083/jcb.200602142. PMC 2064308Freely accessible. PMID 16943182.
  7. 1 2 Sanui T, Inayoshi A, Noda M, et al. (October 2003). "DOCK2 regulates Rac activation and cytoskeletal reorganization through interaction with ELMO1". Blood. 102 (8): 2948–50. doi:10.1182/blood-2003-01-0173. PMID 12829596.
  8. 1 2 Nishihara H, Maeda M, Oda A, et al. (December 2002). "DOCK2 associates with CrkL and regulates Rac1 in human leukemia cell lines". Blood. 100 (12): 3968–74. doi:10.1182/blood-2001-11-0032. PMID 12393632.
  9. ↑ 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.
  10. 1 2 Katoh H, Negishi M (July 2003). "RhoG activates Rac1 by direct interaction with the Dock180-binding protein Elmo". Nature. 424 (6947): 461–64. doi:10.1038/nature01817. PMID 12879077.
  11. ↑ Lu M, Kinchen JM, Rossman KL, et al. (2004). "PH domain of ELMO functions in trans to regulate Rac activation via Dock180". Nature Structural & Molecular Biology. 11 (8): 756–62. doi:10.1038/nsmb800. PMID 15247908.
  12. 1 2 Sai J, Raman D, Liu Y, et al. (July 2008). "Parallel PI3K-dependent and Src-dependent pathways lead to CXCL8- mediated Rac2 activation and chemotaxis". J. Biol. Chem. Article in press (39): 26538–47. doi:10.1074/jbc.M805611200. PMC 2546539Freely accessible. PMID 18662984.
  13. 1 2 Fukui Y, Hashimoto O, Sanui T, et al. (August 2001). "Haematopoietic cell-specific CDM family protein DOCK2 is essential for lymphocyte migration". Nature. 412 (6849): 826–31. doi:10.1038/35090591. PMID 11518968.
  14. 1 2 Gotoh K, Tanaka Y, Nishikimi A, et al. (March 2008). "Differential requirement for DOCK2 in migration of plasmacytoid dendritic cells versus myeloid dendritic cells". Blood. 111 (6): 2973–76. doi:10.1182/blood-2007-09-112169. PMID 18198348.
  15. ↑ Nombela-Arrieta C, Mempel TR, Soriano SF, et al. (March 2007). "A central role for DOCK2 during interstitial lymphocyte motility and sphingosine-1-phosphate-mediated egress". J. Exp. Med. 204 (3): 497–510. doi:10.1084/jem.20061780. PMC 2137902Freely accessible. PMID 17325199.
  16. ↑ Janardhan A, Swigut T, Hill B, et al. (January 2004). "HIV-1 Nef binds the DOCK2-ELMO1 complex to activate rac and inhibit lymphocyte chemotaxis". PLoS Biol. 2 (1): e6. doi:10.1371/journal.pbio.0020006. PMC 314466Freely accessible. PMID 14737186.
  17. ↑ Nishihara H, Maeda M, Oda A, Tsuda M, Sawa H, Nagashima K, Tanaka S (2002). "DOCK2 associates with CrkL and regulates Rac1 in human leukemia cell lines". Blood. 100 (12): 3968–74. doi:10.1182/blood-2001-11-0032. PMID 12393632.

Further reading

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