Dock9

Dedicator of cytokinesis 9
250px PDB rendering based on 1wg7.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1WG7, 2WM9, 2WMN, 2WMO
Identifiers
Symbols	DOCK9 ; ZIZ1; ZIZIMIN1
External IDs	OMIM: 607325 MGI: 106321 HomoloGene: 41026 GeneCards: DOCK9 Gene
Gene ontology Molecular function • Rho guanyl-nucleotide exchange factor activity • protein binding • Rho GTPase binding Cellular component • cytosol • endomembrane system • membrane Biological process • small GTPase mediated signal transduction • blood coagulation • biological_process • positive regulation of GTPase activity Sources: Amigo / QuickGO
RNA expression pattern
File:PBB GE DOCK9 212538 at tn.png
File:PBB GE DOCK9 215041 s at tn.png
File:PBB GE DOCK9 215238 s at tn.png
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	23348	105445
Ensembl	ENSG00000088387	ENSMUSG00000025558
UniProt	Q9BZ29	E9QMR2
RefSeq (mRNA)	NM_001130048	NM_001081039
RefSeq (protein)	NP_001123520	NP_001074508
Location (UCSC)	Chr 13: 98.79 – 99.09 Mb	Chr 14: 121.54 – 121.8 Mb
PubMed search	[1]	[2]

Dock9 (Dedicator of cytokinesis 9), also known as Zizimin1, is a large (~230 kDa) protein involved in intracellular signalling networks. 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. 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. Dock9, along with other DOCK-C/D subfamily members, can activate Cdc42 in vitro and in vivo via its DHR2 domain. However, Dock9 adopts an autoinhibitory conformation that masks the DHR2 domain in its resting state. 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. 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. 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.