Alternative titles; symbols
HGNC Approved Gene Symbol: DOCK4
Cytogenetic location: 7q31.1 Genomic coordinates (GRCh38): 7:111,726,110-112,206,399 (from NCBI)
Yajnik et al. (2003) identified Dock4 by screening a mouse tumor model for homozygous deletions using representational difference analysis. By positional cloning, EST database analysis, RT-PCR, and 5-prime RACE of a placenta cDNA library, they isolated a human DOCK4 cDNA. The predicted 1,966-amino acid DOCK4 protein is a member of the CDM family of small GTPase regulators and shares extensive homology with DOCK1 (601403). The overall structure of DOCK4 is similar to other CDM family members, with an N-terminal SH3 domain, a central region of extended homology, which includes DOCK homology region-1 (DHR1) and DHR2, and a C-terminal proline-rich region. Northern blot analysis detected an 8.5-kb DOCK4 transcript in most tissues tested, with highest expression in skeletal muscle, prostate, and ovary.
Yajnik et al. (2003) showed that DOCK4 specifically activates RAP GTPase (179520), enhancing the formation of adherens junctions. They identified DOCK4 mutations in a subset of human cancer cell lines, and a recurrent missense mutation in human prostate and ovarian cancers resulted in a protein defective in RAP1 activation. The engulfment defect of C. elegans mutants lacking the CDM gene Ced5 could be rescued by wildtype DOCK4, but not by the mutant allele. Expression of wildtype, but not mutant, DOCK4 in mouse osteosarcoma cells with a deletion of the endogenous gene suppressed growth in soft agar and tumor invasion in vivo. Yajnik et al. (2003) concluded that DOCK4 regulates intercellular junctions and is disrupted during tumorigenesis.
Hiramoto-Yamaki et al. (2010) showed that EPHA2 (176946) interacted with ephexin-4 (ARHGEF16; 618871) in MDA-MB-231 human breast cancer cells, thereby promoting cell migration and invasion. Ephexin-4 acted as a GEF for RHOG (179505) downstream of EPHA2 and interacted with RHOG to activate it. Activated RHOG bound ELMO2 (606421) and recruited a ternary complex of ELMO2, DOCK4 (607679), and EPHA2 to the plasma membrane in MDA-MB-231 cells. DOCK4 promoted migration and invasion of MDA-MB-231 cells at tips of cortactin (CTTN; 164765)-rich protrusions through activation of RAC1 (602048).
Myelodysplastic syndromes (MDSs) are heterogeneous hematologic diseases characterized by refractory cytopenias due to ineffective hematopoiesis. By examining DNA methylation profiles for peripheral blood leukocytes from 21 MDS patients and 9 age-matched controls, Zhou et al. (2011) found significant hypermethylation in MDS leukocytes. Of 152 genes that were commonly hypermethylated in MDS, several were GTPase regulators, including DOCK4, which is located in the commonly deleted chromosome 7q31 region. Gene expression profiling revealed that DOCK4 was silenced in both peripheral leukocytes and marrow stem cells in MDS. Knockdown of DOCK4 via short hairpin RNA reduced erythroid and myeloid colony formation and increased apoptosis in primary bone marrow-derived CD34 (142230)-positive stem cells. Zhou et al. (2011) concluded that aberrant DOCK4 expression may contribute to MDS.
Kobayashi et al. (2014) showed that the pro-rich C terminus of mouse Dock4 promoted migration of human breast cancer cells. The pro-rich region of mouse Dock4 interacted with the SH3 domain of human SH3YL1 (617314), and the interaction promoted Dock4-mediated RAC1 activation and human cell migration. Mutations in the phosphoinositide-binding domain disrupted the ability of SH3YL1 to promote Dock4-mediated cell migration. Depletion of SH3YL1 also suppressed cell migration.
Huang et al. (2019) showed in mice that the scavenger receptor Srb1 (601040) in endothelial cells mediates the delivery of LDL cholesterol into arteries and its accumulation by artery wall macrophages, thereby promoting atherosclerosis. LDL particles were colocalized with Srb1 in endothelial cell intracellular vesicles in vivo, and transcytosis of LDL across endothelial monolayers required its direct binding to Srb1 as well as recruitment of the guanine nucleotide exchange factor Dock4 through an 8-amino-acid cytoplasmic domain of Srb1. Dock4 promoted internalization of Srb1 and transport of LDL by coupling the binding of LDL to Srb1 with activation of Rac1. The expression of Srb1 and Dock4 was increased in atherosclerosis-prone regions of the mouse aorta before lesion formation, and in human atherosclerotic arteries when compared with normal arteries. Huang et al. (2019) concluded that their findings challenged the long-held concept that atherogenesis involves passive movement of LDL across a compromised endothelial barrier and suggested that interventions that inhibit the endothelial delivery of LDL into artery walls may represent a novel therapeutic category in the battle against cardiovascular disease.
Yajnik et al. (2003) determined that the DOCK4 gene contains 53 exons and spans 500 kb.
By genomic sequence analysis, Yajnik et al. (2003) mapped the DOCK4 gene to chromosome 7q31. They mapped the mouse Dock4 gene to chromosome 12.
As an initial screen for DOCK4 mutations in human tumors, Yajnik et al. (2003) sequenced the DOCK4 coding sequence from 44 cancer cell lines representing a broad range of tumor types. DNA specimens from 200 healthy individuals (400 chromosomes) were used to exclude polymorphisms. They identified missense mutations in the DOCK4 gene in ovarian, prostate, glioma, and colorectal cancer cell lines, and all mutations affected residues conserved in other CDM family members.
Hiramoto-Yamaki, N., Takeuchi, S., Ueda, S., Harada, K., Fujimoto, S., Negishi, M. Ephexin4 and EphA2 mediate cell migration through a RhoG-dependent mechanism. J. Cell Biol. 190: 461-477, 2010. [PubMed: 20679435] [Full Text: https://doi.org/10.1083/jcb.201005141]
Huang, L., Chambliss, K. L., Gao, X., Yuhanna, I. S., Behling-Kelly, E., Bergaya, S., Ahmed, M., Michaely, P., Luby-Phelps, K., Darehshouri, A., Xu, L., Fisher, E. A., Ge, W.-P., Mineo, C., Shaul, P. W. SR-B1 drives endothelial cell LDL transcytosis via DOCK4 to promote atherosclerosis. Nature 569: 565-569, 2019. [PubMed: 31019307] [Full Text: https://doi.org/10.1038/s41586-019-1140-4]
Kobayashi, M., Harada, K., Negishi, M., Katoh, H. Dock4 forms a complex with SH3YL1 and regulates cancer cell migration. Cell. Signal. 26: 1082-1088, 2014. [PubMed: 24508479] [Full Text: https://doi.org/10.1016/j.cellsig.2014.01.027]
Yajnik, V., Paulding, C., Sordella, R., McClatchey, A. I., Saito, M., Wahrer, D. C. R., Reynolds, P., Bell, D. W., Lake, R., van den Heuvel, S., Settleman, J., Haber, D. A. DOCK4, a GTPase activator, is disrupted during tumorigenesis. Cell 112: 673-684, 2003. [PubMed: 12628187] [Full Text: https://doi.org/10.1016/s0092-8674(03)00155-7]
Zhou, L., Opalinska, J., Sohal, D., Yu, Y., Mo, Y., Bhagat, T., Abdel-Wahab, O., Fazzari, M., Figueroa, M., Alencar, C., Zhang, J., Kambhampati, S., and 18 others. Aberrant epigenetic and genetic marks are seen in myelodysplastic leukocytes and reveal Dock4 as a candidate pathogenic gene on chromosome 7q. J. Biol. Chem. 286: 25211-25223, 2011. [PubMed: 21532034] [Full Text: https://doi.org/10.1074/jbc.M111.235028]