Dock8

Dedicator of cytokinesis 8
Identifiers
Symbols	DOCK8; FLJ00026; FLJ00152; FLJ00346; MRD2; ZIR8
External IDs	OMIM: 611432 MGI: 1921396 HomoloGene: 52414 GeneCards: DOCK8 Gene
Gene Ontology Molecular function • guanyl-nucleotide exchange factor activity • binding • GTP binding • GTPase binding Cellular component • cytosol Biological process • blood coagulation Sources: Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	81704	76088
Ensembl	ENSG00000107099	ENSMUSG00000052085
UniProt	Q8NF50	Q6KAM7
RefSeq (mRNA)	NM_001190458.1	NM_028785.3
RefSeq (protein)	NP_001177387.1	NP_083061.2
Location (UCSC)	Chr 9: 0.21 – 0.47 Mb	Chr 19: 25.07 – 25.28 Mb
PubMed search	[1]	[2]

Dock8 (Dedicator of cytokinesis 8), also known as Zir3, is a large (~190 kDa) protein involved in intracellular signalling networks.^[1] It is a member of the DOCK-C subfamily of the DOCK family of guanine nucleotide exchange factors (GEFs) which function as activators of small G proteins.

Discovery

Dock8 was identified during a yeast two hybrid (YTH) screen for proteins that interact with the Rho family small G protein Cdc42.^[2] Subsequent northern blot analysis revealed high levels of Dock8 expression in the placenta, lung, kidney and pancreas as well as lower levels in the heart, brain and skeletal muscle.

Function

Dock8 shares the same core domain arrangement as all other DOCK proteins, with a DHR2 domain which, in other proteins, contains GEF activity and a DHR1 domain known, in other proteins, to interact with phospholipids. In the YTH system Dock8 was reported to interact with both Rac1 and Cdc42. However, no stable interaction between Dock8 and these small G proteins was observed in a GST-pulldown assay. This may be due to the fact many DOCK-G protein interactions require the presence of adaptor proteins to stabilise the complex and thus facilitate nucleotide exchange.^[3]

Dock8 in disease

Despite the fact that little is known about the cellular role of Dock8 its importance has been highlighted in several studies which have identified distruption of the DOCK8 gene in disease. Deletion and reduced expression of Dock8 have been reported in a human lung cancer cell line^[4] and Dock8 was also identified as a putative candidate gene associated with progression of gliomas.^[5] Interestingly, Dock8 has been reported to be disrupted in two unrelated patients with mental retardation.^[6]

Autosomal recessive DOCK8 deficiency is associated with a variant of combined immunodeficiency. This variant of Hyperimmunoglobulin E syndrome (HIES) was first described in 2004 ^[7] and was now found to have a genetic mutation in the DOCK8 gene.^[8]

References

1. ^ "Entrez Gene: DOCK8 dedicator of cytokinesis 8". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=81704. 
2. ^ Ruusala A, Aspenström P (August 2004). "Isolation and characterisation of DOCK8, a member of the DOCK180-related regulators of cell morphology". FEBS Letters 572 (1-3): 159–66. doi:10.1016/j.febslet.2004.06.095. PMID 15304341. 
3. ^ Lu M, Ravichandran KS (2006). "Dock180-ELMO cooperation in Rac activation". Methods Enzymol. 406: 388–402. doi:10.1016/S0076-6879(06)06028-9. PMID 16472672. 
4. ^ Takahashi K, Kohno T, Ajima R, et al. (February 2006). "Homozygous deletion and reduced expression of the DOCK8 gene in human lung cancer". Int. J. Oncol. 28 (2): 321–28. PMID 16391785. 
5. ^ Idbaih A, Carvalho Silva R, Crinière E, et al. (July 2008). "Genomic changes in progression of low-grade gliomas". J. Neurooncol. Article in press (2): 133–40. doi:10.1007/s11060-008-9644-z. PMID 18618226. 
6. ^ Griggs BL, Ladd S, Saul RA, et al. (February 2008). "Dedicator of cytokinesis 8 is disrupted in two patients with mental retardation and developmental disabilities". Genomics 91 (2): 195. doi:10.1016/j.ygeno.2007.10.011. PMC 2245991. PMID 18060736. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2245991. 
7. ^ Renner ED, Puck JM, Holland SM, Schmitt M, Weiss M, Frosch M, Bergmann M, Davis J, Belohradsky BH, Grimbacher B (2004). "Autosomal recessive hyperimmunoglobulin E syndrome: a distinct disease entity". J Pediatr. 144 (1): 93–9. doi:10.1016/S0022-3476(03)00449-9. PMID 14722525. 
8. ^ Zhang Q, Davis JC, Lamborn IT, Freeman AF, Jing H, Favreau AJ, Matthews HF, Davis J, Turner ML, Uzel G, Holland SM, Su HC (September 2009). "Combined Immunodeficiency Associated with DOCK8 Mutations". N. Engl. J. Med. 361 (21): 2046–55. doi:10.1056/NEJMoa0905506. PMC 2965730. PMID 19776401. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2965730. Lay summary – nih.gov/news. 

Further reading

• Côté JF, Vuori K (2003). "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. 
• 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2887429. 
• Meller N, Merlot S, Guda (2005). "CZH proteins: a new family of Rho-GEFs". J. Cell Sci. 118 (Pt21): 4937–46. doi:10.1242/jcs.02671. PMID 16254241. 
• Côté JF, Vuori K (2006). "In vitro guanine nucleotide exchange activity of DHR-2/DOCKER/CZH2 domains". Methods Enzymol. 406: 41–57. doi:10.1016/S0076-6879(06)06004-6. PMID 16472648. 
• Humphray SJ, Oliver K, Hunt AR, et al. (2004). "DNA sequence and analysis of human chromosome 9.". Nature 429 (6990): 369–74. doi:10.1038/nature02465. PMC 2734081. PMID 15164053. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2734081.