{{Short description|Protein found in humans}} {{cs1 config|name-list-style=vanc}} {{Infobox_gene}} '''Dedicator of cytokinesis protein 9''' ('''Dock9'''), also known as '''Zizimin1''', is a large (~230 kDa) protein encoded in the human by the ''DOCK9'' gene, involved in intracellular signalling networks.<ref name="entrez">{{cite web | title = Entrez Gene: DOCK9 dedicator of cytokinesis 9| url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=23348}}</ref> It is a member of the DOCK-D subfamily of the DOCK family of guanine nucleotide exchange factors that function as activators of small G-proteins. Dock9 activates the small G protein Cdc42.
==Discovery== Dock9 was discovered using an affinity proteomic approach designed to identify novel activators of the small G protein Cdc42 in fibroblasts.<ref name="Meller_2002">{{cite journal | vauthors = Meller N, Irani-Tehrani M, Kiosses WB| title = Zizimin1, a novel Cdc42 activator, reveals a new GEF domain for Rho proteins| journal = Nat. Cell Biol. | volume = 4 | issue = 9 | pages = 639–47|date=September 2002 | pmid = 12172552 | doi = 10.1038/ncb835| s2cid = 24507862|display-authors=etal}}</ref> Subsequent northern blot analysis revealed that Dock9 is expressed primarily in the brain, heart, skeletal muscle, kidney, placenta and lung. Lower levels were detected in the colon, thymus, liver, small intestine and in leukocytes from peripheral blood.
==Structure and function== Dock9 shares a similar structure of two core domains (known as DHR1 and DHR2), which are shared by all DOCK family members. The C-terminal DHR2 domain functions as an atypical GEF domain for small G proteins (see Dock180: structure and function) and the DHR1 domain is known, in some DOCK-A/B/C subfamily proteins, to be involved in their recruitment to the plasma membrane. Unlike DOCK-A/B/C proteins DOCK-D proteins (including Dock9) contain an N-terminal pleckstrin homology (PH) domain that mediates their recruitment to the membrane.<ref name="Meller_2008">{{cite journal | vauthors = Meller N, Westbrook MJ, Shannon JD| title = Function of the N-terminus of zizimin1: autoinhibition and membrane targeting| journal = Biochem. J. | volume = 409 | issue = 2 | pages = 525–33|date=January 2008 | pmid = 17935486 | doi = 10.1042/BJ20071263| pmc = 2740492 |display-authors=etal}}</ref> Dock9, along with other DOCK-C/D subfamily members, can activate Cdc42 ''in vitro'' and ''in vivo'' via its DHR2 domain.<ref name="Meller_2002"/> However, Dock9 adopts an autoinhibitory conformation that masks the DHR2 domain in its resting state.<ref name="Meller_2008"/> The mechanism by which this autoinhibition is overcome is still unclear although in some other DOCK proteins, which also undergo autoinhibition, it requires an interaction with adaptor proteins such as ELMO.<ref name="Lu_2004">{{cite journal | vauthors = Lu M, Kinchen JM, Rossman KL| title = PH domain of ELMO functions in trans to regulate Rac activation via Dock180| journal = Nat. Struct. Mol. Biol. | volume = 11 | issue = 8 | pages = 756–62|date=August 2004 | pmid = 15247908 | doi = 10.1038/nsmb800| s2cid = 125990|display-authors=etal}}</ref><ref name="Lu_2005">{{cite journal | vauthors = Lu M, Kinchen JM, Rossman KL| title = A Steric-inhibition model for regulation of nucleotide exchange via the Dock180 family of GEFs| journal = Curr. Biol. | volume = 15 | issue = 4 | pages = 371–77|date=February 2005 | pmid = 15723800 | doi = 10.1016/j.cub.2005.01.050|display-authors=etal| doi-access = free| bibcode = 2005CBio...15..371L}}</ref> Dock9 has also been reported to dimerise, under resting conditions, via its DHR2 domains and this study suggests that other DOCK family proteins may also behave in the same way.<ref name="Meller_2004">{{cite journal | vauthors = Meller N, Irani-Tehrani M, Ratnikov BI| title = The novel Cdc42 guanine nucleotide exchange factor, zizimin1, dimerizes via the Cdc42-binding CZH2 domain| journal = J. Biol. Chem. | volume = 279 | issue = 36 | pages = 37470–76|date=September 2004 | pmid = 15247287 | doi = 10.1074/jbc.M404535200|display-authors=etal| doi-access = free}}</ref> Recent analysis of a chromosomal region associated with susceptibility to bipolar disorder revealed that single nucleotide polymorphisms in the ''DOCK9'' gene contribute to the risk and severity of this condition.<ref name="Detera-Wadleigh_2007">{{cite journal | vauthors = Detera-Wadleigh SD, Liu CY, Maheshwari M| title = Sequence variation in DOCK9 and heterogeneity in bipolar disorder| journal = Psychiatr. Genet. | volume = 17 | issue = 5 | pages = 274–86|date=October 2007 | pmid = 17728666 | doi = 10.1097/YPG.0b013e328133f352| s2cid = 7102906| url = https://zenodo.org/record/1234913|display-authors=etal}}</ref>
==References== {{Reflist|2}}
==Further reading== {{refbegin | 2}} *{{cite journal | vauthors=Nakajima D, Okazaki N, Yamakawa H |title=Construction of expression-ready cDNA clones for KIAA genes: manual curation of 330 KIAA cDNA clones. |journal=DNA Res. |volume=9 |issue= 3 |pages= 99–106 |year= 2003 |pmid= 12168954 |doi=10.1093/dnares/9.3.99 |display-authors=etal|doi-access=free }} *{{cite journal | vauthors=Kwofie MA, Skowronski J |title=Specific recognition of Rac2 and Cdc42 by DOCK2 and DOCK9 guanine nucleotide exchange factors. |journal=J. Biol. Chem. |volume=283 |issue= 6 |pages= 3088–96 |year= 2008 |pmid= 18056264 |doi= 10.1074/jbc.M705170200 |doi-access= free }} *{{cite journal | vauthors=Meller N, Westbrook MJ, Shannon JD |title=Function of the N-terminus of zizimin1: autoinhibition and membrane targeting. |journal=Biochem. J. |volume=409 |issue= 2 |pages= 525–33 |year= 2008 |pmid= 17935486 |doi= 10.1042/BJ20071263 | pmc=2740492 |display-authors=etal}} *{{cite journal | vauthors=Detera-Wadleigh SD, Liu CY, Maheshwari M |title=Sequence variation in DOCK9 and heterogeneity in bipolar disorder. |journal=Psychiatr. Genet. |volume=17 |issue= 5 |pages= 274–86 |year= 2007 |pmid= 17728666 |doi= 10.1097/YPG.0b013e328133f352 |s2cid=7102906 |display-authors=etal|url=https://zenodo.org/record/1234913 }} *{{cite journal | vauthors=Gerhard DS, Wagner L, Feingold EA |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121–7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504 | pmc=528928 |display-authors=etal}} *{{cite journal | vauthors=Dunham A, Matthews LH, Burton J |title=The DNA sequence and analysis of human chromosome 13. |journal=Nature |volume=428 |issue= 6982 |pages= 522–8 |year= 2004 |pmid= 15057823 |doi= 10.1038/nature02379 | pmc=2665288 |bibcode=2004Natur.428..522D |display-authors=etal}} *{{cite journal | vauthors=Ota T, Suzuki Y, Nishikawa T |title=Complete sequencing and characterization of 21,243 full-length human cDNAs. |journal=Nat. Genet. |volume=36 |issue= 1 |pages= 40–5 |year= 2004 |pmid= 14702039 |doi= 10.1038/ng1285 |display-authors=etal|doi-access=free }} *{{cite journal | vauthors=Strausberg RL, Feingold EA, Grouse LH |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899–903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 | pmc=139241 |bibcode=2002PNAS...9916899M |display-authors=etal|doi-access=free }} *{{cite journal | vauthors=Côté JF, Vuori K |title=Identification of an evolutionarily conserved superfamily of DOCK180-related proteins with guanine nucleotide exchange activity. |journal=J. Cell Sci. |volume=115 |issue= Pt 24 |pages= 4901–13 |year= 2003 |pmid= 12432077 |doi=10.1242/jcs.00219 |doi-access= |s2cid=14669715 }} *{{cite journal | vauthors=Meller N, Irani-Tehrani M, Kiosses WB |title=Zizimin1, a novel Cdc42 activator, reveals a new GEF domain for Rho proteins. |journal=Nat. Cell Biol. |volume=4 |issue= 9 |pages= 639–47 |year= 2002 |pmid= 12172552 |doi= 10.1038/ncb835 |s2cid=24507862 |display-authors=etal}} *{{cite journal | vauthors=Kikuno R, Nagase T, Ishikawa K |title=Prediction of the coding sequences of unidentified human genes. XIV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. |journal=DNA Res. |volume=6 |issue= 3 |pages= 197–205 |year= 1999 |pmid= 10470851 |doi=10.1093/dnares/6.3.197 |display-authors=etal|doi-access=free }} {{refend}} {{PDB Gallery|geneid=23348}}
Category:Biology of bipolar disorder Category:Genes on human chromosome 13
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