DOCK1 (Dedicator of cytokinesis 1)

2015-03-01   Ping Li , Fung Zhao , Annie N. Cheung 

Departments of Pathology, the University of Hong Kong Shenzhen Hospital, Shenzhen (PL, ANC),, The University of Hong Kong, Hong Kong (FZ, AC), China




Dedicator of cytokinesis (DOCK) is a family of proteins with 11 members in mammal which can regulate cell motility, phagocytosis, myoblast fusion, tumor suppression, neuronal polarization and adhesion. They are classified into four subfamilies A to D. Dock1 (Dock180), the founding member of the family, is a large protein which includes an N-terminal SH3 domain and a flanking helical bundle that are vital to the formation of a functioning complex Dock1-ELMO1 (Gumienny et al.,2001; Grimsley et al.,2004; Komander et al., 2008). Genetic and biochemical studies show that DOCK1 acts as a guanine-nucleotide exchange factor (GEF) for the small GTPase Rac1 (Diyokawa et al., 1998; Nolan et al., 1998). Rac1 is a small GTPase required for myoblast fusion in organisms such as fruit flies, zebrafish and mice (Rochlin et al., 1998). In addition to playing an important role in a broad spectrum of biological processes, numerous studies have demonstrated contributions of DOCK members to the development of cancer. Deciphering the detailed mechanisms by which DOCK proteins participate in tumorigenesis will shed light on the design of new treatment strategies.



The DOCK1 gene is 6797 base pairs in length encoding a large protein (about 180kDa).


Variant (1) represents the longer transcript and encodes the longer isoform (1). Variant (2) uses an alternate splice site at an internal exon, compared to variant 1. The encoded isoform (2) is shorter, compared to isoform 1.


Atlas Image
"This research was originally published in Journal of Biological Chemistry. Premkumar L, et al. Structural basis of membrane targeting by the DOCK180 family of Rho family guanine exchange factors (Rho-GEFs). J Biol Chem. 2010, 23; 285(17):13211-22. copyright the American Society for Biochemistry and Molecular Biology." (Premkumar L et al., 2010)


Dock1 is a 180 kDa protein and largely responsible for regulating Rac-mediated polarization, migration, phagocytosis of apoptotic cells, myoblasts fusion and macrophages in vitro (Cte etal., 2005; Grimsley etal., 2004; Pajcini et al., 2008) DOCK1 and its homologues in Drosophila (Myoblast city) and C.elegans (CED-5) represent an evolutionarily conserved family of proteins which is called CDM (CED-5, DOCK180, MBC)-family (Wu and Horvitz, 1998). DOCK1 has 6 splice variants with two protein-coding transcripts generating products consisting of 1865 and 1886 amino acids respectively. The others are non-protein-coding transcripts. An SH3 domain at the A- terminus and two domain CRK-binding sequences at the carboxyl end have been identified in Dock1 (Hideki Hasegawa et al, 1996). There are two high sequence homology named DHR-1 and DHR-2 among Dock family members (Jean Francois Cote and Kristiina Vuori, 2002). DHR1 domain is 200-250 amino acids long that binds phospholipids, whereas DHR2 domain of 450-550 amino acids is responsible for the guanine nucleotide exchange activity (25022758). , SH3 domains src-homology3 (SH3) domains are protein-protein interaction modules in intracellular signal transduction. DOCK1 contains an SH3 domain at its N-terminus. SH3 domains have been reported to bind to a proline-finch motif at the C-terminus of ELMO (gumienny et al., 2001) which will be regulating the activation status of DOCK1. In DOCK1, SH3 domain interacts with DHR-2 domain directly which is dependent on a proline-rich region in DHR-2 domain, but inhibits some functions of the DHR-2 domain, such as binding to nucleotide-free Rac and facilitating GTP loading(Lu et al., 2005).
 , Interaction with ELMO ELMO is an evolutionarily conserved upstream regulator of Rac that takes effect at the same step as DOCK 1 in phagocytosis of apoptotic cells and cell migration (Gumienny et al., 2001). DOCK2-5 and DOCK 1 have an amino-terminal Src homology (SH)-3 domain which can interact with ELMO proteins and cooperate to activate Rac (Grimsley et al., 2004; Hiramoto et al., 2006). Other Dock-related proteins such as DOCK 6-8 and DOCK9-11 cannot physically interact with ELMO proteins due to the lack of a recognizable SH3 domain. Some studies showed that deletion mutants of DOCK 180 that fail to bind to ELMO could not efficiently activate Rac even when over-expressed in cells (Grimsley et al., 2004). Other studies suggested that owing to auto-inhibition, the isolated DHR-2 appears to have much higher GEF activity than total DOCK 180 (Lu et al., 2005; Cote et al., 2007). Co-expression of ELMO is required to relieve the auto-inhibited state (Lu et al., 2004; Santy et al., 2005). The ELMO-DOCK1 complex is located in the cytoplasm and will be translocated to the cell membrane, which is the key step for DOCK1 to activate Rac (Debakker et al., 2004; Katoh and Negishi et al., 2003; Hasegawa et al., 1996; Katoh et al., 2006). All three mammalian ELMO 1-3 proteins have no obvious catalytic activity. They have three recognizable features including armadillo repeats at the N-terminus, an atypical PH domain and a complex prolin-rich region at the C-terminus. In fact, the functions of ELMO proteins in mediating Rac signaling remain largely unknown, and the interaction between ELMO and DOCK is still unclear. Some data indicate that there are two contact regions between DOCK1 and ELMO1. The atypical ELMO1 PH domain and an uncharacterized region between the SH3 and DHR-1 domains primarily interact with each other. This interaction is sufficient to promote complex formation. N-terminal SH3 domain of DOCK1 and the C-terminal PxxP motifs of ELMO1 are involved in the second contact (Komander et al., 2008). The PH domain and proline-rich motifs are implicated in binding to DOCK protein (Manishha et al., 2011). It has been documented that the SH3 domain of DOCK1 binds to a proline-rich (pro-rich) motif at the C-terminus of ELMO, and this in turn would activate DOCK 1. This is the second interaction. So when either of these motifs is mutated, the interaction of ELMO and DOCK1 is completely interrupted (Gumienny et al., 2011; Lu et al., 2005). The PH domain of ELMO stabilizes the DOCK1-nucleotide-free Rac complex through binding "in trans" instead of interacting directly with either Rac or DOCK 180 (Lu et al, 2004). The atypical PH domain of ELMO plays a crucial role in increasing the catalytic activity of DOCK 180 towards Rac. ELMO1 or ELMO2, could coexpress with DOCK1, and overexpression of ELMO1 together with DOCK1 synergistically enhances phagocytosis(Zhou et al., 2001). ELMO PH domain could slightly enhance the catalytic activity of DOCK 1 toward Rac by about twofold in vitro. But this effect could be efficient in vivo because the Ced-12 PH domain mutations let Ced-12-null worms failed to rescue the migration defects (Lu et al., 2004). Therefore, the mechanism of action of Elmo remains inconclusive. Further studies are required to clarify the controversies.
 , Binding to Crk Crk is an adaptor protein consisting mostly of SH2 and SH3 domains which is also involved in signaling processes, such as cell adhesions, differentiation, migration, proliferation, and phagocytosis of apoptotic cells (Clark and Brugge, 1995; Juliano and Haskill, 1993; Richardson and Parsons, 1995). Crk gene can be translated into two proteins, Crk-I and Crk-II which are primarily isolated as oncogenic products (Mayer etal., 1988; Matsuda et al., 1992). DOCK180/DOCK1 can bind with the SH3 of the Crk through PxxP region in its C-termini (Matsuda et al., 1996). It has been shown that DOCK 1 has two C-terminal CRK-binding sequences. DOCK1 binds with Crk on the basis of a biochemical interaction. The complex will be transiently translocated to the membrane resulting in changes in cell morphology (Hasegawa et al., 1996).
 , Essential for myoblast fusion Mammalian myogenesis arises from the fusion of mononucleated myoblasts. Myogenic cells fuse with each other to form multinucleated myotubes (Horsley and Pavlath, 2004). Myoblast fusion is responsible for development during embryogenesis and postnatal maintenance, growth, and helps regenerate injured tissue (Cerletti et al.m 2008; Rudnicki et al., 2008). Proper regulation of myoblast fusion events determines myofiber length, appropriate contractile capacity and muscle function(Allen et al., 1999). In fact, the understanding of myoblast fusion of higher vertebrates remains poor. Current knowledge is largely derived from genetic analyses performed in Drosophila(Chen and Olson, 2004; Taylor, 2003) and in vivo experiments in vertebrates (Cote and Vuori, 2007). In Drosophila melanogaster, fusion-competent myoblasts and founder cells regulate the formation of multinucleate muscle fibers. At cellular level, the processes of myoblast fusion include alignment, actin cytoskeleton rearrangement at the contact sites and membrane fusion (Knudsen and Horwitz, 1977; Wakelam, 1985; Peckham, 2008; Duan and Gallagher, 2009). CDM superfamily consists of founding members such as MBC, human DOCK1, Caenorhabditis elegans CED-5 (Wu and Horvitz, 1998) and almost 20 additional members (Cote and Vuori, 2002). Myoblast city (mbc) is highly important in Drosophila melanogaster embryo for multinucleate fibers formation. It has been reported that Mbc together with ELMO, function as an atypical bipartite GEF to directly control Rac1 in vivo. Drosophila eye experiments show that Mbc and ELMO interaction will increase the activity of Ras (Gersbrecht et al., 2008).


DOCK1 is predominantly located in the cytoplasm of cells. Nuclear localization of DOCK1 has also been reported (Zhao et al., 2011).


This family is one of the GEFs being identified as activators of Rho GTPases (Takai etal., 1996; Hasegawa et al., 1996; Erickson and Cerione, 2004). DOCK1 activates Rho GTPase through facilitating the exchange of bound GDP for GTP. GTPases can regulate actin cytoskeleton and be accountable for crucial biological functions, such as cell phagocytosis, cell migration, cell proliferation, cell survival, cell polarity, axonal guidance, transcription and intracellular trafficking (Iwasato et al., 2007; Schmidt and Hall, 2002). In addition to playing an important role in a broad spectrum of biological processes, numerous studies have demonstrated contribution of DOCK members to the development of cancer.


DHR domain DOCK1 and its homologues in Drosophila (Myoblast city) and C.elegans (CED-5) represent an evolutionarily conserved family of proteins which is called CDM (CED-5, DOCK180, MBC)-family(Wu and Horvitz, 1998). This family is one of the GEFs being identified as activators of Rho GTPases (Takai etal., 1996; Hasegawa et al., 1996; Erickson and Cerione, 2004). The other family is Db1 family (Hart et al., 1991) and all their members contain the Db1 Homology (DH) and the Pleckstrin Homology (PH) domains (Klinger et al., 2004; Srivastava et al., 1986; Worthylake te al., 2004; Feng et al.,2002; Baird et al., 2005). While DH domains directly catalyze GDP-GTP exchange, PH domains target proteins to membranes and mediate protein-protein interactions. DOCK 180-related proteins can catalyze nucleotide exchange without homology to DH/PH domains, which are characterized by two protein domains named DOCK homology regions 1 and 2 (DHR-1 and DHR-2, respectively) (Brugnera et al., 2002; Cote and Vuori, 2002). DOCK1 contains 1864 amino acids, a Src-homology 3 (SH3) domain at the amino terminus, a few proline-rich motifs at the carboxyl terminus and a potential phosphatidylinositol trisphosphate (PtdInsP3)-interacting motif near its C terminus (Hasegawa et al.m 1996; Kobayashi et al 2001). Inactivation of the DHR-2 (also known as CZH2 or DOCKER) in DOCK1 can inhibit Rac activation, cell migration and clearance of apoptotic cells. This demonstrates the necessity and sufficiency of DHR-2 to promote GDP/GTP exchange on various GTPases. DHR-2 has been suggested to consist of about 500 residues (Brugnera et al., 2002; Cote and Vuori, 2002). DHR-2 domains of these family members have been shown to interact with the nucleotide-free form of Rho GTPase leading to the exchange of GDP for GTP(Meller et al., 2004; Lin et al., 2006; Miyamoto et al., 2006; Nishikimi et al 2005). DHR-1 domain (also known as CZH1) is located upstream of DHR-2 domain (Meller et al., 2002) and is a novel PtdIns (3,4,5)P3-binding module which directly interacts with phosphoinositides (PI),playing an important role in Rac-mediated cell polarity and migration including myoblast fusion(Cote and Vuori, 2002).


In mammals, dedicator of cytokinesis (DOCK) represents a new family of proteins comprising 11 members named DOCK1 (also known as Dock180) to Dock11. They are classified into four subfamilies denoted Dock-A, -B, -C, -D. 11 members are classified as following: DOCK-A subfamily (DOCK1, DOCK2 and DOCK5); DOCK-B subfamily (DOCK3 and DOCK4); DOCK-C subfamily (DOCK6, DOCK7 and DOCK8); DOCK-D subfamily (DOCK9, DOCK10 and DOCK11) (Bridget Biersmith et al, 2011).

Implicated in

Entity name
Breast cancer
Expression of DOCK1 correlates with poor survival for HER2+ and basal breast cancer patients (Eckhardt et al., 2012; Perou et al., 2000). Dock1 protein interacts with HER2 and enhances HER2-induced Rac activation and cell migration (Laurin et al., 2013).
Entity name
EGFR8, a constitutively active EGFR mutant, promotes glioma tumorigenesis and invasion through protein kinase A-dependent phosphorylation of DOCK1 (Feng H et al, 2014).
Entity name
Ovarian cancer
Correlation of high Dock1 expression with poor survival for patients has been reported. Dock1 overexpression contributes to enhanced ovarian cancer cell migration and invasion (Zhao F et al, 2011).
Entity name
Lung cancer
Dock1 can upregulate PTTG which could play a role in actin cytoskeleton remodeling, cell migration and induction of epithelial mesenchymal transition in lung cancer. The integrin alpha(V)beta(3)-FAK (focal adhesion kinase) signaling pathway is involved. (Shah PP et al, 2012).
Entity name
Gastric cancer
Among genes involved in extracellular signal-regulated kinase (ERK) downstream signaling pathways activated by Cytotoxin-associated antigen (CagA), a H. pylori immunoprotein, single nucleotide polymorphism of Dock1 was found to be significantly associated with risk of developing gastric cancer with marginal gene dose effects. (Yang JJ et al, 2011).


Pubmed IDLast YearTitleAuthors
104879001999Myonuclear domains in muscle adaptation and disease.Allen DL et al
156493572005The Cool-2/alpha-Pix protein mediates a Cdc42-Rac signaling cascade.Baird D et al
121341582002Unconventional Rac-GEF activity is mediated through the Dock180-ELMO complex.Brugnera E et al
147444292004Rho and Rac take center stage.Burridge K et al
177655442007GEF what? Dock180 and related proteins help Rac to polarize cells in new ways.Côté JF et al
192040652008Regulation and function of skeletal muscle stem cells.Cerletti M et al
153082122004Towards a molecular pathway for myoblast fusion in Drosophila.Chen EH et al
77165141995Integrins and signal transduction pathways: the road taken.Clark EA et al
90874411997Genetic analysis of myoblast fusion: blown fuse is required for progression beyond the prefusion complex.Doberstein SK et al
190270002009Dependence of myoblast fusion on a cortical actin wall and nonmuscle myosin IIA.Duan R et al
226532172012Strategies for the discovery and development of therapies for metastatic breast cancer.Eckhardt BL et al
147441252004Structural elements, mechanism, and evolutionary convergence of Rho protein-guanine nucleotide exchange factor complexes.Erickson JW et al
237283372014EGFRvIII stimulates glioma growth and invasion through PKA-dependent serine phosphorylation of Dock180.Feng H et al
117419312002Regulation of the Cool/Pix proteins: key binding partners of the Cdc42/Rac targets, the p21-activated kinases.Feng Q et al
153068502004Novel regulatory mechanisms for the Dbl family guanine nucleotide exchange factor Cool-2/alpha-Pix.Feng Q et al
181639872008Drosophila ELMO/CED-12 interacts with Myoblast city to direct myoblast fusion and ommatidial organization.Geisbrecht ER et al
146386952004Dock180 and ELMO1 proteins cooperate to promote evolutionarily conserved Rac-dependent cell migration.Grimsley CM et al
115951832001CED-12/ELMO, a novel member of the CrkII/Dock180/Rac pathway, is required for phagocytosis and cell migration.Gumienny TL et al
19563811991Catalysis of guanine nucleotide exchange on the CDC42Hs protein by the dbl oncogene product.Hart MJ et al
86571521996DOCK180, a major CRK-binding protein, alters cell morphology upon translocation to the cell membrane.Hasegawa H et al
170279672006Dock4 is regulated by RhoG and promotes Rac-dependent cell migration.Hiramoto K et al
177195502007Rac-GAP alpha-chimerin regulates motor-circuit formation as a key mediator of EphrinB3/EphA4 forward signaling.Iwasato T et al
83811171993Signal transduction from the extracellular matrix.Juliano RL et al
128790772003RhoG activates Rac1 by direct interaction with the Dock180-binding protein Elmo.Katoh H et al
98086201998Activation of Rac1 by a Crk SH3-binding protein, DOCK180.Kiyokawa E et al
149916102004The RhoA- and CDC42-specific exchange factor Dbs promotes expansion of immature thymocytes and deletion of double-positive and single-positive thymocytes.Klinger MB et al
8852921977Tandem events in myoblast fusion.Knudsen KA et al
111710812001Membrane recruitment of DOCK180 by binding to PtdIns(3,4,5)P3.Kobayashi S et al
187687512008An alpha-helical extension of the ELMO1 pleckstrin homology domain mediates direct interaction to DOCK180 and is critical in Rac signaling.Komander D et al
235927192013Rac-specific guanine nucleotide exchange factor DOCK1 is a critical regulator of HER2-mediated breast cancer metastasis.Laurin M et al
169686982006Identification of a DOCK180-related guanine nucleotide exchange factor that is capable of mediating a positive feedback activation of Cdc42.Lin Q et al
157238002005A Steric-inhibition model for regulation of nucleotide exchange via the Dock180 family of GEFs.Lu M et al
16304561992Two species of human CRK cDNA encode proteins with distinct biological activities.Matsuda M et al
152472872004The novel Cdc42 guanine nucleotide exchange factor, zizimin1, dimerizes via the Cdc42-binding CZH2 domain.Meller N et al
171969612007Dock6, a Dock-C subfamily guanine nucleotide exchanger, has the dual specificity for Rac1 and Cdc42 and regulates neurite outgrowth.Miyamoto Y et al
147185412004MOCA induces membrane spreading by activating Rac1.Namekata K et al
119119702002Molecular and immunohistochemical analysis of signaling adaptor protein Crk in human cancers.Nishihara H et al
157103882005Zizimin2: a novel, DOCK180-related Cdc42 guanine nucleotide exchange factor expressed predominantly in lymphocytes.Nishikimi A et al
98086211998Myoblast city, the Drosophila homolog of DOCK180/CED-5, is required in a Rac signaling pathway utilized for multiple developmental processes.Nolan KM et al
183322212008Myoblasts and macrophages share molecular components that contribute to cell-cell fusion.Pajcini KV et al
222921302011Opening up on ELMO regulation: New insights into the control of Rac signaling by the DOCK180/ELMO complex.Patel M et al
187550042008Engineering a multi-nucleated myotube, the role of the actin cytoskeleton.Peckham M et al
109636022000Molecular portraits of human breast tumours.Perou CM et al
201676012010Structural basis of membrane targeting by the Dock180 family of Rho family guanine exchange factors (Rho-GEFs).Premkumar L et al
77481771995Signal transduction through integrins: a central role for focal adhesion kinase?Richardson A et al
199322062010Myoblast fusion: when it takes more to make one.Rochlin K et al
156880022005GEF means go: turning on RHO GTPases with guanine nucleotide-exchange factors.Rossman KL et al
193295722008The molecular regulation of muscle stem cell function.Rudnicki MA et al
162138222005The DOCK180/Elmo complex couples ARNO-mediated Arf6 activation to the downstream activation of Rac1.Santy LC et al
121011192002Guanine nucleotide exchange factors for Rho GTPases: turning on the switch.Schmidt A et al
220810742012PTTG induces EMT through integrin αVβ3-focal adhesion kinase signaling in lung cancer cells.Shah PP et al
34913661986Identification of the protein encoded by the human diffuse B-cell lymphoma (dbl) oncogene.Srivastava SK et al
86611601996Chromosomal mapping of the gene encoding DOCK180, a major Crk-binding protein, to 10q26.13-q26.3 by fluorescence in situ hybridization.Takai S et al
146806552003Muscle differentiation: signalling cell fusion.Taylor MV et al
38908351985The fusion of myoblasts.Wakelam MJ et al
152749272004Crystal structure of the DH/PH fragment of Dbs without bound GTPase.Worthylake DK et al
95482551998C. elegans phagocytosis and cell-migration protein CED-5 is similar to human DOCK180.Wu YC et al
126281872003DOCK4, a GTPase activator, is disrupted during tumorigenesis.Yajnik V et al
216981582011Oncogenic CagA promotes gastric cancer risk via activating ERK signaling pathways: a nested case-control study.Yang JJ et al
221758962011Overexpression of dedicator of cytokinesis I (Dock180) in ovarian cancer correlated with aggressive phenotype and poor patient survival.Zhao F et al
117039392001The C. elegans PH domain protein CED-12 regulates cytoskeletal reorganization via a Rho/Rac GTPase signaling pathway.Zhou Z et al
156206472004Phagocytosis of apoptotic cells is regulated by a UNC-73/TRIO-MIG-2/RhoG signaling module and armadillo repeats of CED-12/ELMO.deBakker CD et al

Other Information

Locus ID:

NCBI: 1793
MIM: 601403
HGNC: 2987
Ensembl: ENSG00000150760


dbSNP: 1793
ClinVar: 1793
TCGA: ENSG00000150760


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Focal adhesionKEGGko04510
Regulation of actin cytoskeletonKEGGko04810
Focal adhesionKEGGhsa04510
Regulation of actin cytoskeletonKEGGhsa04810
Bacterial invasion of epithelial cellsKEGGko05100
Bacterial invasion of epithelial cellsKEGGhsa05100
Immune SystemREACTOMER-HSA-168256
Innate Immune SystemREACTOMER-HSA-168249
Fcgamma receptor (FCGR) dependent phagocytosisREACTOMER-HSA-2029480
Regulation of actin dynamics for phagocytic cup formationREACTOMER-HSA-2029482
Factors involved in megakaryocyte development and platelet productionREACTOMER-HSA-983231
Signal TransductionREACTOMER-HSA-162582
Signaling by VEGFREACTOMER-HSA-194138
Developmental BiologyREACTOMER-HSA-1266738
Axon guidanceREACTOMER-HSA-422475
Netrin-1 signalingREACTOMER-HSA-373752
DCC mediated attractive signalingREACTOMER-HSA-418885
Signaling by PTK6REACTOMER-HSA-8848021
PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinasesREACTOMER-HSA-8849471

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
121341582002Unconventional Rac-GEF activity is mediated through the Dock180-ELMO complex.191
124320772002Identification of an evolutionarily conserved superfamily of DOCK180-related proteins with guanine nucleotide exchange activity.133
146386952004Dock180 and ELMO1 proteins cooperate to promote evolutionarily conserved Rac-dependent cell migration.85
160251042005A novel and evolutionarily conserved PtdIns(3,4,5)P3-binding domain is necessary for DOCK180 signalling.85
162138222005The DOCK180/Elmo complex couples ARNO-mediated Arf6 activation to the downstream activation of Rac1.72
163854512006A scan of chromosome 10 identifies a novel locus showing strong association with late-onset Alzheimer disease.69
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
171730362007Shigella IpgB1 promotes bacterial entry through the ELMO-Dock180 machinery.57
187255412008uPAR promotes formation of the p130Cas-Crk complex to activate Rac through DOCK180.55
220808642011Activation of Rac1 by Src-dependent phosphorylation of Dock180(Y1811) mediates PDGFRα-stimulated glioma tumorigenesis in mice and humans.49


Ping Li ; Fung Zhao ; Annie N. Cheung

DOCK1 (Dedicator of cytokinesis 1)

Atlas Genet Cytogenet Oncol Haematol. 2015-03-01

Online version: