Dedicator of cytokinesis protein 1 explained

Dedicator of cytokinesis protein 1 (Dock1), also (DOCK180), is a large (~180 kDa) protein encoded in the human by the DOCK1 gene, involved in intracellular signalling networks.^[1] It is the mammalian ortholog of the C. elegans protein CED-5 and belongs to the DOCK family of guanine nucleotide exchange factors (GEFs).^[2]

Discovery

DOCK180 was identified, using a far-western blotting approach, as a binding partner of the adaptor protein Crk that was able to induce morphological changes in 3T3 fibroblasts.^[3] Subsequently it was reported that DOCK180 was able to activate the small GTP-binding protein (G protein) Rac1^[4] and this was later shown to happen via its ability to act as a GEF.^[5]

Structure and function

DOCK180 is part of a large class of proteins (GEFs) which contribute to cellular signalling events by activating small G proteins. In their resting state G proteins are bound to Guanosine diphosphate (GDP) and their activation requires the dissociation of GDP and binding of guanosine triphosphate (GTP). GEFs activate G proteins by promoting this nucleotide exchange.

DOCK180 and related proteins differ from other GEFs in that they do not possess the canonical structure of tandem DH-PH domains known to elicit nucleotide exchange. Instead they possess a DHR2 domain which mediates Rac activation by stabilising it in its nucleotide-free state.^[5] DOCK180-related proteins also possess a DHR1 domain which has been shown, in vitro, to bind phospholipids^[6] and which may be involved in their interaction with cellular membranes. Other structural features of Dock180 include an N-terminal SH3 domain involved in binding to ELMO proteins (see below)^[7] and a C-terminal proline-rich region which, in Myoblast city (the Drosophila melanogaster ortholog of DOCK180), was shown to bind DCrk (the Drosophila ortholog of Crk).^[8]

Regulation of DOCK180 Activity

Under physiological conditions DOCK180 alone is inefficient at promoting nucleotide exchange on Rac.^[7] Effective GEF activity requires an interaction between Dock180 and its binding partner ELMO. ELMO1 is the most comprehensively described isoform of this small family of non-catalytically active proteins which function to recruit Dock180 to the plasma membrane and induce conformational changes which increase GEF efficiency.^{[9] [10] [11]} ELMO1 has also been reported to inhibit ubiquitinylation of Dock180 and so prevent its degradation by proteasomes.^[12] Receptor-mediated activation of RhoG (a small G protein of the Rac subfamily) is perhaps the best known inducer of Dock180 GEF activity. Active (GTP-bound) RhoG recruits the ELMO/Dock180 complex to the plasma membrane thereby bringing Dock180 into contact with its substrate, Rac.^[13] In tumour cells DOCK180 is regulated by a complex containing Crk and p130Cas which is in turn regulated by cooperative signalling by β₃-containing integrin complexes and the membrane-bound protein uPAR.^[14]

Signalling Downstream of DOCK180

DOCK180 is a Rac-specific GEF and so is responsible for a subset of Rac-specific signalling events. These include cell migration and phagocytosis of apoptotic cells in C. elegans,^[15] neurite outgrowth in PC12 cells^[16] and myoblast fusion in the zebrafish embryo.^[17] More recently the DHR1 domain of DOCK180 was shown to bind SNX5 (a sorting nexin) and this interaction promoted retrograde transport of the cation-independent mannose 6-phosphate receptor to the trans-Golgi network in a Rac-independent manner.^[18] Increased expression of DOCK180 and Elmo has been reported to contribute to glioma invasion.^[19]

Interactions

DOCK180 has been shown to interact with:

• BCAR1,^[20]
• CRK^{[20] [21] [22] [23]}
• ELMO1,^{[24] [25]} and
• Grb2.^{[20] [26]}

Further reading

• Takai S, Hasegawa H, Kiyokawa E . Chromosomal mapping of the gene encoding DOCK180, a major Crk-binding protein, to 10q26.13-q26.3 by fluorescence in situ hybridization . Genomics . 35 . 2 . 403–4 . 1996 . 8661160 . 10.1006/geno.1996.0378 . etal.
• Côté JF, Vuori K . GEF what? Dock180 and related proteins help Rac to polarize cells in new ways . Trends Cell Biol. . 17 . 8 . 383–93 . 2007 . 17765544 . 2887429 . 10.1016/j.tcb.2007.05.001 .
• Komander D, Patel M, Laurin M . An α-Helical Extension of the ELMO1 Pleckstrin Homology Domain Mediates Direct Interaction to DOCK180 and Is Critical in Rac Signaling . Mol. Biol. Cell . 19 . 11. 4837–51. 2008 . 18768751 . 10.1091/mbc.E08-04-0345 . 2575150 . etal.
• Henson PM . Engulfment: ingestion and migration with Rac, Rho and TRIO . Curr. Biol. . 15 . 1 . R29–30 . 2005 . 15649349 . 10.1016/j.cub.2004.12.017 . free . 2005CBio...15..R29H .
• deBakker CD, Haney LB, Kinchen JM . Phagocytosis of apoptotic cells is regulated by a UNC-73/TRIO-MIG-2/RhoG signaling module and armadillo repeats of CED-12/ELMO . Curr. Biol. . 14 . 24 . 2208–16 . 2004 . 15620647 . 10.1016/j.cub.2004.12.029 . 1269946 . etal. free . 2004CBio...14.2208D .
• Yin J, Haney L, Walk S . Nuclear localization of the DOCK180/ELMO complex . Arch. Biochem. Biophys. . 429 . 1 . 23–29 . 2004 . 15288806 . 10.1016/j.abb.2004.05.014 . etal .
• Matsuda M, Ota S, Tanimura R . Interaction between the amino-terminal SH3 domain of CRK and its natural target proteins . J. Biol. Chem. . 271 . 24 . 14468–72 . 1996 . 8662907 . 10.1074/jbc.271.24.14468 . etal. free .
• Savill J . Apoptosis. Phagocytic docking without shocking . Nature . 392 . 6675 . 442–3 . 1998 . 9548247 . 10.1038/33025 . 1998Natur.392..442S . 205002296 . free .
• Wu YC, Horvitz HR . C. elegans phagocytosis and cell-migration protein CED-5 is similar to human DOCK180 . Nature . 392 . 6675 . 501–4 . 1998 . 9548255 . 10.1038/33163 . 1998Natur.392..501W . 205002377 .
• Albert ML, Kim JI, Birge RB . alphavbeta5 integrin recruits the CrkII-Dock180-rac1 complex for phagocytosis of apoptotic cells . Nat. Cell Biol. . 2 . 12 . 899–905 . 2001 . 11146654 . 10.1038/35046549 . 7535200 .
• Kobayashi S, Shirai T, Kiyokawa E . Membrane recruitment of DOCK180 by binding to PtdIns(3,4,5)P3 . Biochem. J. . 354 . Pt 1 . 73–8 . 2001 . 11171081 . 10.1042/0264-6021:3540073 . 1221630 . etal.
• Tu Y, Kucik DF, Wu C . Identification and kinetic analysis of the interaction between Nck-2 and DOCK180 . FEBS Lett. . 491 . 3 . 193–9 . 2001 . 11240126 . 10.1016/S0014-5793(01)02195-0 . 31372015 . free . 2001FEBSL.491..193T .
• Gu J, Sumida Y, Sanzen N, Sekiguchi K . Laminin-10/11 and fibronectin differentially regulate integrin-dependent Rho and Rac activation via p130(Cas)-CrkII-DOCK180 pathway . J. Biol. Chem. . 276 . 29 . 27090–7 . 2001 . 11369773 . 10.1074/jbc.M102284200 . free .
• Zhou Z, Caron E, Hartwieg E . The C. elegans PH domain protein CED-12 regulates cytoskeletal reorganization via a Rho/Rac GTPase signaling pathway . Dev. Cell . 1 . 4 . 477–89 . 2001 . 11703939 . 10.1016/S1534-5807(01)00058-2 . etal. free .
• Grimsley CM, Kinchen JM, Tosello-Trampont AC . Dock180 and ELMO1 proteins cooperate to promote evolutionarily conserved Rac-dependent cell migration . J. Biol. Chem. . 279 . 7 . 6087–97 . 2004 . 14638695 . 10.1074/jbc.M307087200 . 2324987 . etal . free .
• Wang X, Wu YC, Fadok VA . Cell corpse engulfment mediated by C. elegans phosphatidylserine receptor through CED-5 and CED-12 . Science . 302 . 5650 . 1563–6 . 2003 . 14645848 . 10.1126/science.1087641 . 2003Sci...302.1563W . 25672278 . etal .

External links

• • DOCK180 Info with links in the Cell Migration Gateway

Notes and References

1. Web site: Entrez Gene: DOCK1 dedicator of cytokinesis 1.
2. Meller N, Merlot S, Guda C . CZH proteins: a new family of Rho-GEFs . J. Cell Sci. . 118 . Pt 21 . 4937–46 . November 2005 . 16254241 . 10.1242/jcs.02671. 3075895 .
3. Hasegawa H, Kiyokawa E, Tanaka S . DOCK180, a major CRK-binding protein, alters cell morphology upon translocation to the cell membrane . Mol. Cell. Biol. . 16 . 4 . 1770–76 . April 1996 . 8657152 . 10.1128/mcb.16.4.1770. 231163 . etal.
4. Kiyokawa E, Hashimoto Y, Kobayashi S . Activation of Rac1 by a Crk SH3-binding protein, DOCK180 . Genes Dev. . 12 . 21 . 3331–36 . November 1998 . 9808620 . 10.1101/gad.12.21.3331. 317231 . etal.
5. Côté JF, Vuori K . Identification of an evolutionarily conserved superfamily of DOCK180-related proteins with guanine nucleotide exchange activity . J. Cell Sci. . 115 . Pt 24 . 4901–13 . December 2002 . 12432077 . 10.1242/jcs.00219. 14669715 .
6. Côté JF, Motoyama AB, Bush JA . A novel and evolutionarily conserved PtdIns(3,4,5)P3-binding domain is necessary for DOCK180 signaling. Nat. Cell Biol. . 7 . 8 . 797–807 . August 2005 . 16025104 . 10.1038/ncb1280. 1352170 . etal.
7. Brugnera E, Haney L, Grimsley C . Unconventional Rac-GEF activity is mediated through the Dock180-ELMO complex. Nat. Cell Biol. . 4 . 8 . 574–82 . August 2002 . 12134158 . 10.1038/ncb824. 36363774. etal.
8. Balagopalan L, Chen MH, Geisbrecht ER . The CDM Superfamily Protein MBC Directs Myoblast Fusion through a Mechanism That Requires Phosphatidylinositol 3,4,5-Triphosphate Binding but Is Independent of Direct Interaction with DCrk. Mol. Cell. Biol. . 26 . 24 . 9442–55 . December 2006 . 17030600 . 10.1128/MCB.00016-06. 1698515 . etal.
9. Book: Lu M, Ravichandran KS . Dock180–ELMO Cooperation in Rac Activation. Regulators and Effectors of Small GTPases: Rho Family. 406 . 388–402 . 2006 . 16472672 . 10.1016/S0076-6879(06)06028-9. Methods in Enzymology. 978-0-12-182811-0.
10. Lu M, Kinchen JM, Rossman KL . PH domain of ELMO functions in trans to regulate Rac activation via Dock180. Nature Structural & Molecular Biology . 11 . 8 . 756–62 . 2004 . 15247908 . 10.1038/nsmb800. 125990. etal.
11. Lu M, Kinchen JM, Rossman KL . A Steric-inhibition model for regulation of nucleotide exchange via the Dock180 family of GEFs. Curr. Biol. . 15 . 4 . 371–77 . February 2005 . 15723800 . 10.1016/j.cub.2005.01.050. 14267018. etal. free . 2005CBio...15..371L.
12. Makino Y, Tsuda M, Ichihara S . Elmo1 inhibits ubiquitylation of Dock180. J. Cell Sci. . 119 . Pt 5 . 923–32 . March 2006 . 16495483 . 10.1242/jcs.02797. 15035869. etal.
13. Katoh H, Negishi M. RhoG activates Rac1 by direct interaction with the Dock180-binding protein Elmo. Nature . 424 . 6947 . 461–64 . July 2003 . 12879077 . 10.1038/nature01817. 2003Natur.424..461K. 4411133.
14. Smith HW, Marra P, Marshall CJ. uPAR promotes formation of the p130Cas–Crk complex to activate Rac through DOCK180. J. Cell Biol. . 182 . 4 . 777–90 . August 2008 . 18725541 . 10.1083/jcb.200712050. 2518715 .
15. Gumienny TL, Brugnera E, Tosello-Trampont AC . CED-12/ELMO, a novel member of the CrkII/Dock180/Rac pathway, is required for phagocytosis and cell migration . Cell . 107 . 1 . 27–41 . October 2001 . 11595183 . 10.1016/S0092-8674(01)00520-7 . 15232864 . etal . 2020-09-13 . 2021-09-22 . https://web.archive.org/web/20210922225900/https://www.zora.uzh.ch/id/eprint/952/1/Gumienny2001V.pdf . dead .
16. Katoh H, Yasui H, Yamaguchi Y. Small GTPase RhoG Is a Key Regulator for Neurite Outgrowth in PC12 Cells. Mol. Cell. Biol. . 20 . 19 . 7378–87 . October 2000 . 10982854 . 10.1128/MCB.20.19.7378-7387.2000. 86291 . etal.
17. Moore CA, Parkin CA, Bidet Y. A role for the Myoblast city homologues Dock1 and Dock5 and the adaptor proteins Crk and Crk-like in zebrafish myoblast fusion. Development . 134 . 17 . 3145–53 . September 2007 . 17670792 . 10.1242/dev.001214. etal. free .
18. Hara S, Kiyokawa E, Iemura SI. The DHR1 Domain of DOCK180 Binds to SNX5 and Regulates Cation-independent Mannose 6-phosphate Receptor Transport. Mol. Biol. Cell . 19 . 9. 3823–35. July 2008 . 18596235 . 10.1091/mbc.E08-03-0314. 2526700 . etal.
19. Jarzynka MJ, Hu B, Hui KM. ELMO1 and Dock180, a Bipartite Rac1 Guanine Nucleotide Exchange Factor, Promote Human Glioma Cell Invasion. Cancer Res. . 67 . 15 . 7203–11 . August 2007 . 17671188 . 10.1158/0008-5472.CAN-07-0473. 2867339 . etal.
20. Mar 2003 . Hsia DA, Mitra SK, Hauck CR, Streblow DN, Nelson JA, Ilic D, Huang S, Li E, Nemerow GR, Leng J, Spencer KS, Cheresh DA, Schlaepfer DD . Differential regulation of cell motility and invasion by FAK . J. Cell Biol. . 160 . 5 . 753–67 . 12615911 . 2173366 . 10.1083/jcb.200212114.
21. Nov 1999 . Nishihara H, Kobayashi S, Hashimoto Y, Ohba F, Mochizuki N, Kurata T, Nagashima K, Matsuda M . Non-adherent cell-specific expression of DOCK2, a member of the human CDM-family proteins . Biochim. Biophys. Acta . 1452 . 2 . 179–87 . 10559471 . 10.1016/s0167-4889(99)00133-0. free .
22. Jul 2001 . Gu J, Sumida Y, Sanzen N, Sekiguchi K . Laminin-10/11 and fibronectin differentially regulate integrin-dependent Rho and Rac activation via p130(Cas)-CrkII-DOCK180 pathway . J. Biol. Chem. . 276 . 29 . 27090–7 . 11369773 . 10.1074/jbc.M102284200. free .
23. Jun 1996 . Matsuda M, Ota S, Tanimura R, Nakamura H, Matuoka K, Takenawa T, Nagashima K, Kurata T . Interaction between the amino-terminal SH3 domain of CRK and its natural target proteins . J. Biol. Chem. . 271 . 24 . 14468–72 . 8662907 . 10.1074/jbc.271.24.14468. free .
24. Oct 2001 . Gumienny TL, Brugnera E, Tosello-Trampont AC, Kinchen JM, Haney LB, Nishiwaki K, Walk SF, Nemergut ME, Macara IG, Francis R, Schedl T, Qin Y, Van Aelst L, Hengartner MO, Ravichandran KS . CED-12/ELMO, a novel member of the CrkII/Dock180/Rac pathway, is required for phagocytosis and cell migration . Cell . 107 . 1 . 27–41 . 11595183 . 10.1016/s0092-8674(01)00520-7 . 15232864 . 2020-09-13 . 2021-09-22 . https://web.archive.org/web/20210922225900/https://www.zora.uzh.ch/id/eprint/952/1/Gumienny2001V.pdf . dead .
25. Aug 2002 . Brugnera E, Haney L, Grimsley C, Lu M, Walk SF, Tosello-Trampont AC, Macara IG, Madhani H, Fink GR, Ravichandran KS . Unconventional Rac-GEF activity is mediated through the Dock180-ELMO complex . Nat. Cell Biol. . 4 . 8 . 574–82 . 12134158 . 10.1038/ncb824. 36363774 .
26. Apr 1996 . 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 cell membrane . Mol. Cell. Biol. . 16 . 4 . 1770–6 . 8657152 . 231163 . 10.1128/MCB.16.4.1770.