Dock2

Dock2
Dedicator of cytokinesis 2

Rendering based on PDB 2RQR.
Identifiers
Symbols DOCK2; FLJ46592; KIAA0209
External IDs OMIM603122 MGI2149010 HomoloGene37984 GeneCards: DOCK2 Gene
RNA expression pattern
PBB GE DOCK2 213160 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 1794 94176
Ensembl ENSG00000134516 ENSMUSG00000020143
UniProt Q92608 Q5SRI4
RefSeq (mRNA) NM_004946 NM_033374.2
RefSeq (protein) NP_004937 NP_203538.2
Location (UCSC) Chr 5:
169.06 – 169.51 Mb
Chr 11:
34.13 – 34.6 Mb
PubMed search [1] [2]

Dock2 (Dedicator of cytokinesis 2), also known as DOCK2, is a large (~180 kDa) protein involved in intracellular signalling networks.[1] 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.

Contents

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.[2]

Structure and Function

Dock2 is part of a large class of proteins (GEFs) which contibrute 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.[3] They also contain a DHR1 domain which binds phospholipids and is required for the interaction between Dock2 and the plasma membrane.[4] 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).[5] Dock180 contains a C-terminal proline rich region which mediates binding to Crk, however, Dock2 lacks this feature[2] despite the fact that it is able to bind the Crk-like protein CrkL.[6]

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.[7][8] 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.[5] 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).[8] ELMO proteins also contain a PH domain which appears to induce conformational changes in DOCK and thus allow binding to Rac.[9]

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.[2] 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[4] and is also important for chemotaxis in neutrophils,[4][10] lymphocytes[11] and plasmacytoid dendritic cells.[12] Dock2-dependent NADPH oxidase activation was reported in response to the soluble agonist fMLP, which acts via G protein-coupled receptors in neutrophils.[4] 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[11] as well as CCL21/SLC in ex vivo plasmacytoid dendritic cells.[12] In neutrophil chemotaxis Dock2 signals downstream of the C5a and CXCL8/IL-8 receptors.[4][10] Additional receptors which signal through Dock2 include the T cell receptor/TCR[6] and EDG1, a sphingosine-1-phosphate (S1P) receptor.[13] 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.[14]

Interactions

Dock2 has been shown to interact with CRKL.[15]

References

  1. ^ "Entrez Gene: DOCK2 dedicator of cytokinesis 2". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1794. 
  2. ^ a b c 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. 
  3. ^ 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. 
  4. ^ a b c d e 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 2064308. PMID 16943182. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2064308. 
  5. ^ a b 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. 
  6. ^ a b 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. 
  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 231163. PMID 8657152. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=231163. 
  8. ^ a b 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. 
  9. ^ Lu M, Kinchen JM, Rossman KL, et al. (2004). "PH domain of ELMO functions in trans to regulate Rac activation via Dock180". Nat. Struc. Mol. Biol. 11 (8): 756–62. doi:10.1038/nsmb800. PMID 15247908. 
  10. ^ a b 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 2546539. PMID 18662984. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2546539. 
  11. ^ a b 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. 
  12. ^ a b 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. 
  13. ^ 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 2137902. PMID 17325199. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2137902. 
  14. ^ 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 314466. PMID 14737186. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=314466. 
  15. ^ Nishihara, Hiroshi; Maeda Masae, Oda Atsushi, Tsuda Masumi, Sawa Hirofumi, Nagashima Kazuo, Tanaka Shinya (Dec. 2002). "DOCK2 associates with CrkL and regulates Rac1 in human leukemia cell lines". Blood (United States) 100 (12): 3968–74. doi:10.1182/blood-2001-11-0032. ISSN 0006-4971. PMID 12393632. 

Further reading



Wikimedia Foundation. 2010.

Игры ⚽ Поможем написать реферат

Look at other dictionaries:

  • ELMO1 — Engulfment and cell motility 1, also known as ELMO1, is a human gene.cite web | title = Entrez Gene: ELMO1 engulfment and cell motility 1| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene Cmd=ShowDetailView TermToSearch=9844| accessdate = ] …   Wikipedia

  • Rac2 — (Ras related C3 botulinum toxin substrate 2) is a small ( 21 kDa) signaling G protein (more specifically a GTPase), and is a member of the Rac subfamily of the family Rho family of GTPases.cite journal |author=Ridley A. |year=2006 |title=Rho… …   Wikipedia

  • Dock180 — Dedicator of cytokinesis 1 Identifiers Symbols DOCK1; DOCK180; ced5 External IDs OMI …   Wikipedia

  • RhoG — (Ras homology Growth related) (or ARGH) is a small ( 21 kDa) monomeric GTP binding protein (G protein), and is an important component of many intracellular signalling pathways. It is a member of the Rac subfamily of the Rho family of small G… …   Wikipedia

  • Dock4 — Dedicator of cytokinesis 4 Identifiers Symbols DOCK4; FLJ34238; KIAA0716; MGC134911; MGC134912 External IDs …   Wikipedia

  • Dock9 — Dedicator of cytokinesis 9 PDB rendering based on 1wg7 …   Wikipedia

  • DOCK (protein) — Zir redirects here. For other uses, see Zir (disambiguation) Dedicator of cytokinesis Identifiers Symbol Ded cyto Pfam PF06920 InterPro …   Wikipedia

  • Nef (protein) — Negative factor, (F Protein) or Nef NMR structure of the NEF protein based on the PDB 2NEF coordinates. Identifiers Symbol …   Wikipedia

  • Dock5 — Dedicator of cytokinesis 5 Identifiers Symbols DOCK5; DKFZp451J181; DKFZp779M164; DKFZp781J211 External IDs …   Wikipedia

  • Dock6 — Dedicator of cytokinesis 6 Identifiers Symbols DOCK6; ZIR1 External IDs MGI:&# …   Wikipedia

Share the article and excerpts

Direct link
Do a right-click on the link above
and select “Copy Link”