Alternative titles; symbols
HGNC Approved Gene Symbol: DOCK1
Cytogenetic location: 10q26.2 Genomic coordinates (GRCh38): 10:126,905,428-127,452,516 (from NCBI)
DOCK1 belongs to a family of guanine-nucleotide exchange factors that activate the small G proteins RAC (see 602048) and/or CDC42 (116952) (Sanders et al., 2009).
The CRK protein (164762) has an important role in signaling from focal adhesions. Along with other adaptor proteins, such as GRB2 (108355) and NCK (600508), CRK receives signals through its SH2 domains from phosphotyrosine-containing peptides and transfers them to other proteins bound to its SH3 domains. Among proteins that bind to the SH3 domain of CRK are C3G (600303), a guanine nucleotide exchange protein for RAP1 (179520), and a 180-kD protein designated DOCK180. Hasegawa et al. (1996) isolated a cDNA for DOCK180 by screening an expression library with CRK SH3. The full-length DOCK180 cDNA that encodes a putative 1,866-amino acid polypeptide with an N-terminal SH3 domain. Northern blot analysis detected a 7.6-kb transcript in most tissues examined, with strongest expression in placenta, lung, kidney, and pancreas. Wildtype DOCK180 was found in cytoplasm and did not affect cell morphology. However, when farnesylated, the protein became associated with the cytoplasmic membrane and made spindle 3T3 cells become flattened and polygonal.
During programmed cell death (apoptosis), cell corpses are rapidly engulfed. This engulfment process involves the recognition and subsequent phagocytosis of cell corpses by engulfing cells. Wu and Horvitz (1998) shed light on the previously obscure mechanisms by which cell corpses are engulfed. They reported that ced-5, a gene that is required for cell-corpse engulfment in the nematode Caenorhabditis elegans, encodes a protein that is similar to the human protein DOCK180 and the Drosophila melanogaster protein Myoblast City (MBC), both of which had been implicated in the extension of cell surfaces. C. elegans ced-5 mutants were defective not only in the engulfment of cell corpses but also in the migrations of 2 specific gonadal cells, the distal tip cells. The expression of human DOCK180 in C. elegans rescued the cell-migration defect of a ced-5 mutant. Wu and Horvitz (1998) presented evidence that ced-5 functions in engulfing cells during the engulfment of cell corpses. They suggested that ced-5 acts in the extension of the surface of an engulfing cell around a dying cell during programmed cell death. They named the new family of proteins that function in the extension of cell surfaces the CDM (for CED-5, DOCK180, and MBC) family.
Savill (1998) summarized understanding of how CED-5 and CD14 (158120), together with other molecules function in the engulfment of cell corpses by macrophages in the process of programmed cell death. The model incorporated the newly proposed functions of CED-5 and CD14.
Cote and Vuori (2002) found that the isolated DOCK homology region-2 (DHR2; amino acids 1111-1636) of human DOCK180 bound and activated RAC in vitro and in 293T and LR73 Chinese hamster ovary cells. ELMO1 (606420) coexpression was not necessary for this activity.
Katoh and Negishi (2003) demonstrated that RHO G (179505) interacts directly with ELMO2 (606421) in a GTP-dependent manner and forms a ternary complex with DOCK180 to induce activation of RAC1 (602048). The RHO G-ELMO2-DOCK180 pathway is required for activation of RAC1 and cell spreading mediated by integrin, as well as for neurite outgrowth induced by nerve growth factor. Katoh and Negishi (2003) concluded that RHO G activates RAC1 through ELMO and DOCK180 to control cell morphology.
Park et al. (2007) identified brain-specific angiogenesis inhibitor-1 (BAI1; 602682) as a receptor upstream of ELMO and as a receptor that can bind phosphatidylserine on apoptotic cells. BAI1 is a 7-transmembrane protein belonging to the adhesion-type G protein-coupled receptor family with an extended extracellular region. Park et al. (2007) showed that BAI1 functions as an engulfment receptor in both the recognition and subsequent internalization of apoptotic cells. Through multiple lines of investigation, Park et al. (2007) identified phosphatidylserine, a key 'eat-me' signal exposed on apoptotic cells, as a ligand for BAI1. The thrombospondin type 1 (188060) repeats within the extracellular region of BAI1 mediate direct binding to phosphatidylserine. As with intracellular signaling, BAI1 forms a trimeric complex with ELMO and Dock180, and functional studies suggested that BAI1 cooperates with ELMO/Dock180/Rac to promote maximal engulfment of apoptotic cells. Last, Park et al. (2007) found that decreased BAI1 expression or interference with BAI1 function inhibited the engulfment of apoptotic targets ex vivo and in vivo. Thus, Park et al. (2007) concluded that BAI1 is a phosphatidylserine recognition receptor that can directly recruit a Rac-GEF complex to mediate the uptake of apoptotic cells.
Sanders et al. (2009) found that knockdown of DOCK1 or DOCK5 (616904) via small interfering RNA in Caco2 human intestinal epithelial cells partly reduced cell spreading and migration on collagen IV (see 120130). Knockdown of both DOCK1 and DOCK5 synergistically inhibited cell spreading in Caco2 or human umbilical vein endothelial cells. CRKII (CRK; 164762) and CRKL (602007) were required for the effects of DOCK1 and DOCK5 on cell spreading.
Takai et al. (1996) mapped DOCK180 to chromosome 10q26.13-q26.3 by fluorescence in situ hybridization.
Gross (2016) mapped the DOCK1 gene to chromosome 10q26.2 based on an alignment of the DOCK1 sequence (GenBank BC146857) with the genomic sequence (GRCh38).
Cote, J.-F., Vuori, K. Identification of an evolutionarily conserved superfamily of DOCK180-related proteins with guanine nucleotide exchange activity. J. Cell Sci. 115: 4901-4913, 2002. [PubMed: 12432077] [Full Text: https://doi.org/10.1242/jcs.00219]
Gross, M. B. Personal Communication. Baltimore, Md. 8/31/2016.
Hasegawa, H., Kiyokawa, E., Tanaka, S., Nagashima, K., Gotoh, N., Shibuya, M., Kurata, T., Matsuda, M. DOCK180, a major CRK-binding protein, alters cell morphology upon translocation to the membrane. Molec. Cell Biol. 16: 1770-176, 1996. [PubMed: 8657152] [Full Text: https://doi.org/10.1128/MCB.16.4.1770]
Katoh, H., Negishi, M. RhoG activates Rac1 by direct interaction with the Dock180-binding protein Elmo. Nature 424: 461-464, 2003. [PubMed: 12879077] [Full Text: https://doi.org/10.1038/nature01817]
Park, D., Tosello-Trampont, A.-C., Elliott, M. R., Lu, M., Haney, L. B., Ma, Z., Klibanov, A. L., Mandell, J. W., Ravichandran, K. S. BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module. Nature 450: 430-434, 2007. [PubMed: 17960134] [Full Text: https://doi.org/10.1038/nature06329]
Sanders, M. A., Ampasala, D., Basson, M. D. DOCK5 and DOCK1 regulate Caco-2 intestinal epithelial cell spreading and migration on collagen IV. J. Biol. Chem. 284: 27-35, 2009. [PubMed: 19004829] [Full Text: https://doi.org/10.1074/jbc.M808010200]
Savill, J. Phagocytic docking without shocking. Nature 392: 442-443, 1998. [PubMed: 9548247] [Full Text: https://doi.org/10.1038/33025]
Takai, S., Hasegawa, H., Kiyokawa, E., Yamada, K., Kurata, T., Matsuda, M. Chromosomal mapping of the gene encoding DOCK180, a major Crk-binding protein, to 10q26.13-q26.3 by fluorescence in situ hybridization. Genomics 35: 403-404, 1996. [PubMed: 8661160] [Full Text: https://doi.org/10.1006/geno.1996.0378]
Wu, Y.-C., Horvitz, H. R. C. elegans phagocytosis and cell-migration protein CED-5 is similar to human DOCK180. Nature 392: 501-504, 1998. [PubMed: 9548255] [Full Text: https://doi.org/10.1038/33163]