Atlas of Genetics and Cytogenetics in Oncology and Haematology

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DOCK1 (Dedicator of cytokinesis 1) 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

Published in Atlas Database: March 2015 Online updated version : http://AtlasGeneticsOncology.org/Genes/DOCK1ID40354ch10q26.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62524/03-2015-DOCK1ID40354ch10q26.pdf DOI: 10.4267/2042/62524 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2016 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Abstract DNA/RNA Dedicator of cytokinesis (DOCK) is a family of Description proteins with 11 members in mammal which can The DOCK1 gene is 6797 base pairs in length regulate cell motility, phagocytosis, myoblast fusion, encoding a large protein (about 180kDa). tumor suppression, neuronal polarization and adhesion. They are classified into four subfamilies A Transcription to D. Dock1 (), the founding member of the Variant (1) represents the longer transcript and family, is a large protein which includes an N- encodes the longer isoform (1). terminal SH3 domain and a flanking helical bundle Variant (2) uses an alternate splice site at an internal that are vital to the formation of a functioning exon, compared to variant 1. complex Dock1-ELMO1 (Gumienny et al.,2001; The encoded isoform (2) is shorter, compared to Grimsley et al.,2004; Komander et al., 2008). isoform 1. Genetic and biochemical studies show that DOCK1 acts as a guanine-nucleotide exchange factor (GEF) Protein for the small GTPase Rac1 (Diyokawa et al., 1998; Nolan et al., 1998). Rac1 is a small GTPase required Description for myoblast fusion in organisms such as fruit flies, Dock1 is a 180 kDa protein and largely responsible zebrafish and mice (Rochlin et al., 1998). In addition for regulating Rac-mediated polarization, migration, to playing an important role in a broad spectrum of phagocytosis of apoptotic cells, myoblasts fusion biological processes, numerous studies have and macrophages in vitro (Cte etal., 2005; Grimsley demonstrated contributions of DOCK members to etal., 2004; Pajcini et al., 2008) DOCK1 and its the development of cancer. Deciphering the detailed homologues in Drosophila (Myoblast city) and mechanisms by which DOCK proteins participate in C.elegans (CED-5) represent an evolutionarily tumorigenesis will shed light on the design of new conserved family of proteins which is called CDM treatment strategies. (CED-5, DOCK180, MBC)-family (Wu and Keywords Horvitz, 1998). DOCK1 DOCK1 has 6 splice variants with two protein- coding transcripts generating products consisting of Identity 1865 and 1886 amino acids respectively. The others are non-protein-coding transcripts. Other names: ced5, DOCK 180 An SH3 domain at the A- terminus and two domain HGNC (Hugo): DOCK1 CRK-binding sequences at the carboxyl end have Location: 10q26.13-q26.3 been identified in Dock1 (Hideki Hasegawa et al, 1996).

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"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)

There are two high sequence homology named and 2 (DHR-1 and DHR-2, respectively) (Brugnera DHR-1 and DHR-2 among Dock family members et al., 2002; Cote and Vuori, 2002). DOCK1 contains (Jean Francois Cote and Kristiina Vuori, 2002). 1864 amino acids, a Src-homology 3 (SH3) domain DHR1 domain is 200-250 amino acids long that at the amino terminus, a few proline-rich motifs at binds phospholipids, whereas DHR2 domain of 450- the carboxyl terminus and a potential 550 amino acids is responsible for the guanine phosphatidylinositol trisphosphate (PtdInsP3)- nucleotide exchange activity (25022758). interacting motif near its C terminus (Hasegawa et Expression al.m 1996; Kobayashi et al 2001). Inactivation of the DHR-2 (also known as CZH2 or DOCKER) in DOCK1 is predominantly located in the cytoplasm DOCK1 can inhibit Rac activation, cell migration of cells. Nuclear localization of DOCK1 has also and clearance of apoptotic cells. This demonstrates been reported (Zhao et al., 2011). the necessity and sufficiency of DHR-2 to promote Function GDP/GTP exchange on various GTPases. DHR-2 This family is one of the GEFs being identified as has been suggested to consist of about 500 residues activators of Rho GTPases (Takai etal., 1996; (Brugnera et al., 2002; Cote and Vuori, 2002). DHR- Hasegawa et al., 1996; Erickson and Cerione, 2004). 2 domains of these family members have been DOCK1 activates Rho GTPase through facilitating shown to interact with the nucleotide-free form of the exchange of bound GDP for GTP. GTPases can Rho GTPase leading to the exchange of GDP for regulate actin cytoskeleton and be accountable for GTP(Meller et al., 2004; Lin et al., 2006; Miyamoto crucial biological functions, such as cell et al., 2006; Nishikimi et al 2005). DHR-1 domain phagocytosis, cell migration, cell proliferation, cell (also known as CZH1) is located upstream of DHR- survival, cell polarity, axonal guidance, transcription 2 domain (Meller et al., 2002) and is a novel PtdIns and intracellular trafficking (Iwasato et al., 2007; (3,4,5)P3-binding module which directly interacts Schmidt and Hall, 2002). In addition to playing an with phosphoinositides (PI),playing an important important role in a broad spectrum of biological role in Rac-mediated cell polarity and migration processes, numerous studies have demonstrated including myoblast fusion(Cote and Vuori, 2002). contribution of DOCK members to the development SH3 domains src-homology3 (SH3) domains are of cancer. protein-protein interaction modules in intracellular signal transduction. DOCK1 contains an SH3 Description domain at its N-terminus. SH3 domains have been DHR domain DOCK1 and its homologues in reported to bind to a proline-finch motif at the C- Drosophila (Myoblast city) and C.elegans (CED-5) terminus of ELMO (gumienny et al., 2001) which represent an evolutionarily conserved family of will be regulating the activation status of DOCK1. In proteins which is called CDM (CED-5, DOCK180, DOCK1, SH3 domain interacts with DHR-2 domain MBC)-family(Wu and Horvitz, 1998). This family is directly which is dependent on a proline-rich region one of the GEFs being identified as activators of Rho in DHR-2 domain, but inhibits some functions of the GTPases (Takai etal., 1996; Hasegawa et al., 1996; DHR-2 domain, such as binding to nucleotide-free Erickson and Cerione, 2004). The other family is Rac and facilitating GTP loading(Lu et al., 2005). Db1 family (Hart et al., 1991) and all their members Interaction with ELMO ELMO is an evolutionarily contain the Db1 Homology (DH) and the Pleckstrin conserved upstream regulator of Rac that takes effect Homology (PH) domains (Klinger et al., 2004; at the same step as DOCK 1 in phagocytosis of Srivastava et al., 1986; Worthylake te al., 2004; Feng apoptotic cells and cell migration (Gumienny et al., et al.,2002; Baird et al., 2005). While DH domains 2001). -5 and DOCK 1 have an amino- directly catalyze GDP-GTP exchange, PH domains terminal Src homology (SH)-3 domain which can target proteins to membranes and mediate protein- interact with ELMO proteins and cooperate to protein interactions. DOCK 180-related proteins can activate Rac (Grimsley et al., 2004; Hiramoto et al., catalyze nucleotide exchange without homology to 2006). Other Dock-related proteins such as DOCK DH/PH domains, which are characterized by two 6-8 and DOCK9-11 cannot physically interact with protein domains named DOCK homology regions 1 ELMO proteins due to the lack of a recognizable

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SH3 domain. Some studies showed that deletion involved in signaling processes, such as cell mutants of DOCK 180 that fail to bind to ELMO adhesions, differentiation, migration, proliferation, could not efficiently activate Rac even when over- and phagocytosis of apoptotic cells (Clark and expressed in cells (Grimsley et al., 2004). Other Brugge, 1995; Juliano and Haskill, 1993; Richardson studies suggested that owing to auto-inhibition, the and Parsons, 1995). isolated DHR-2 appears to have much higher GEF Crk gene can be translated into two proteins, Crk-I activity than total DOCK 180 (Lu et al., 2005; Cote and Crk-II which are primarily isolated as oncogenic et al., 2007). Co-expression of ELMO is required to products (Mayer etal., 1988; Matsuda et al., 1992). relieve the auto-inhibited state (Lu et al., 2004; Santy DOCK180/DOCK1 can bind with the SH3 of the et al., 2005). The ELMO-DOCK1 complex is located Crk through PxxP region in its C-termini (Matsuda in the cytoplasm and will be translocated to the cell et al., 1996). It has been shown that DOCK 1 has two membrane, which is the key step for DOCK1 to C-terminal CRK-binding sequences. DOCK1 binds activate Rac (Debakker et al., 2004; Katoh and with Crk on the basis of a biochemical interaction. Negishi et al., 2003; Hasegawa et al., 1996; Katoh et The complex will be transiently translocated to the al., 2006). All three mammalian ELMO 1-3 proteins membrane resulting in changes in cell morphology have no obvious catalytic activity. They have three (Hasegawa et al., 1996). recognizable features including armadillo repeats at Essential for myoblast fusion Mammalian the N-terminus, an atypical PH domain and a myogenesis arises from the fusion of mononucleated complex prolin-rich region at the C-terminus. In fact, myoblasts. Myogenic cells fuse with each other to the functions of ELMO proteins in mediating Rac form multinucleated myotubes (Horsley and Pavlath, signaling remain largely unknown, and the 2004). Myoblast fusion is responsible for interaction between ELMO and DOCK is still development during embryogenesis and postnatal unclear. Some data indicate that there are two contact maintenance, growth, and helps regenerate injured regions between DOCK1 and ELMO1. The atypical tissue (Cerletti et al.m 2008; Rudnicki et al., 2008). ELMO1 PH domain and an uncharacterized region Proper regulation of myoblast fusion events between the SH3 and DHR-1 domains primarily determines myofiber length, appropriate contractile interact with each other. This interaction is sufficient capacity and muscle function(Allen et al., 1999). In to promote complex formation. N-terminal SH3 fact, the understanding of myoblast fusion of higher domain of DOCK1 and the C-terminal PxxP motifs vertebrates remains poor. Current knowledge is of ELMO1 are involved in the second contact largely derived from genetic analyses performed in (Komander et al., 2008). The PH domain and Drosophila(Chen and Olson, 2004; Taylor, 2003) proline-rich motifs are implicated in binding to and in vivo experiments in vertebrates (Cote and DOCK protein (Manishha et al., 2011). It has been Vuori, 2007). documented that the SH3 domain of DOCK1 binds In Drosophila melanogaster, fusion-competent to a proline-rich (pro-rich) motif at the C-terminus of myoblasts and founder cells regulate the formation ELMO, and this in turn would activate DOCK 1. of multinucleate muscle fibers. At cellular level, the This is the second interaction. So when either of processes of myoblast fusion include alignment, these motifs is mutated, the interaction of ELMO and actin cytoskeleton rearrangement at the contact sites DOCK1 is completely interrupted (Gumienny et al., and membrane fusion (Knudsen and Horwitz, 1977; 2011; Lu et al., 2005). The PH domain of ELMO Wakelam, 1985; Peckham, 2008; Duan and stabilizes the DOCK1-nucleotide-free Rac complex Gallagher, 2009). CDM superfamily consists of through binding "in trans" instead of interacting founding members such as MBC, human DOCK1, directly with either Rac or DOCK 180 (Lu et al, Caenorhabditis elegans CED-5 (Wu and Horvitz, 2004). The atypical PH domain of ELMO plays a 1998) and almost 20 additional members (Cote and crucial role in increasing the catalytic activity of Vuori, 2002). Myoblast city (mbc) is highly DOCK 180 towards Rac. ELMO1 or ELMO2, could important in Drosophila melanogaster embryo for coexpress with DOCK1, and overexpression of multinucleate fibers formation. ELMO1 together with DOCK1 synergistically It has been reported that Mbc together with ELMO, enhances phagocytosis(Zhou et al., 2001). ELMO function as an atypical bipartite GEF to directly PH domain could slightly enhance the catalytic control Rac1 in vivo. Drosophila eye experiments activity of DOCK 1 toward Rac by about twofold in show that Mbc and ELMO interaction will increase vitro. But this effect could be efficient in vivo the activity of Ras (Gersbrecht et al., 2008). because the Ced-12 PH domain mutations let Ced- Homology 12-null worms failed to rescue the migration defects (Lu et al., 2004). Therefore, the mechanism of action In mammals, dedicator of cytokinesis (DOCK) of Elmo remains inconclusive. Further studies are represents a new family of proteins comprising 11 required to clarify the controversies. members named DOCK1 (also known as Dock180) Binding to Crk Crk is an adaptor protein consisting to Dock11. They are classified into four subfamilies mostly of SH2 and SH3 domains which is also denoted Dock-A, -B, -C, -D. 11 members are

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classified as following: DOCK-A subfamily Burridge K, Wennerberg K. Rho and Rac take center stage. (DOCK1, DOCK2 and DOCK5); DOCK-B Cell. 2004 Jan 23;116(2):167-79 subfamily (DOCK3 and ); DOCK-C Côté JF, Vuori K. GEF what? Dock180 and related proteins subfamily (, and DOCK8); DOCK- help Rac to polarize cells in new ways. Trends Cell Biol. D subfamily (DOCK9, DOCK10 and DOCK11) 2007 Aug;17(8):383-93 (Bridget Biersmith et al, 2011). Cerletti M, Shadrach JL, Jurga S, Sherwood R, Wagers AJ. Regulation and function of skeletal muscle stem cells. Cold Implicated in Spring Harb Symp Quant Biol. 2008;73:317-22 Chen EH, Olson EN. Towards a molecular pathway for Breast cancer myoblast fusion in Drosophila. Trends Cell Biol. 2004 Aug;14(8):452-60 Expression of DOCK1 correlates with poor survival for HER2+ and basal breast cancer patients Clark EA, Brugge JS. Integrins and signal transduction pathways: the road taken. Science. 1995 Apr (Eckhardt et al., 2012; Perou et al., 2000). Dock1 14;268(5208):233-9 protein interacts with HER2 and enhances HER2- Doberstein SK, Fetter RD, Mehta AY, Goodman CS. induced Rac activation and cell migration (Laurin et Genetic analysis of myoblast fusion: blown fuse is required al., 2013). for progression beyond the prefusion complex. J Cell Biol. Glioblastoma 1997 Mar 24;136(6):1249-61 Duan R, Gallagher PJ. Dependence of myoblast fusion on EGFR8, a constitutively active EGFR mutant, a cortical actin wall and nonmuscle myosin IIA. Dev Biol. promotes glioma tumorigenesis and invasion 2009 Jan 15;325(2):374-85 through protein kinase A-dependent Eckhardt BL, Francis PA, Parker BS, Anderson RL. phosphorylation of DOCK1 (Feng H et al, 2014). Strategies for the discovery and development of therapies Ovarian cancer for metastatic breast cancer. Nat Rev Drug Discov. 2012 Jun 1;11(6):479-97 Correlation of high Dock1 expression with poor Erickson JW, Cerione RA. Structural elements, mechanism, survival for patients has been reported. Dock1 and evolutionary convergence of Rho protein-guanine overexpression contributes to enhanced ovarian nucleotide exchange factor complexes. Biochemistry. 2004 cancer cell migration and invasion (Zhao F et al, Feb 3;43(4):837-42 2011). Feng H, Hu B, Vuori K, Sarkaria JN, Furnari FB, Cavenee WK, Cheng SY. EGFRvIII stimulates glioma growth and Lung cancer invasion through PKA-dependent serine phosphorylation of Dock1 can upregulate PTTG which could play a role Dock180. Oncogene. 2014 May 8;33(19):2504-12 in actin cytoskeleton remodeling, cell migration and Feng Q, Albeck JG, Cerione RA, Yang W. Regulation of the induction of epithelial mesenchymal transition in Cool/Pix proteins: key binding partners of the Cdc42/Rac lung cancer. The integrin alpha(V)beta(3)-FAK targets, the p21-activated kinases. J Biol Chem. 2002 Feb 15;277(7):5644-50 (focal adhesion kinase) signaling pathway is involved. (Shah PP et al, 2012). Feng Q, Baird D, Cerione RA. Novel regulatory mechanisms for the Dbl family guanine nucleotide exchange factor Cool- Gastric cancer 2/alpha-Pix. EMBO J. 2004 Sep 1;23(17):3492-504 Among genes involved in extracellular signal- Geisbrecht ER, Haralalka S, Swanson SK, Florens L, Washburn MP, Abmayr SM. Drosophila ELMO/CED-12 regulated kinase (ERK) downstream signaling interacts with Myoblast city to direct myoblast fusion and pathways activated by Cytotoxin-associated antigen ommatidial organization. Dev Biol. 2008 Feb 1;314(1):137- (CagA), a H. pylori immunoprotein, single 49 nucleotide polymorphism of Dock1 was found to be Grimsley CM, Kinchen JM, Tosello-Trampont AC, Brugnera significantly associated with risk of developing E, Haney LB, Lu M, Chen Q, Klingele D, Hengartner MO, gastric cancer with marginal gene dose effects. Ravichandran KS. Dock180 and ELMO1 proteins cooperate (Yang JJ et al, 2011). to promote evolutionarily conserved Rac-dependent cell migration. 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