DOCK180 was identified, using a far-western blotting approach, as a binding partner of the adaptor proteinCrk that was able to induce morphological changes in 3T3 fibroblasts.[7] Subsequently it was reported that DOCK180 was able to activate the small GTP-binding protein (G protein) Rac1[8] and this was later shown to happen via its ability to act as a GEF.[9]
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.[9] DOCK180-related proteins also possess a DHR1 domain which has been shown, in vitro, to bind phospholipids[10] and which may be involved in their interaction with cellular membranes. Other structural features of Dock180 include an N-terminalSH3 domain involved in binding to ELMO proteins (see below)[11] and a C-terminalproline-rich region which, in Myoblast city (the Drosophila melanogaster ortholog of DOCK180), was shown to bind DCrk (the Drosophila ortholog of Crk).[12]
Regulation of DOCK180 Activity
Under physiological conditions DOCK180 alone is inefficient at promoting nucleotide exchange on Rac.[11] 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.[13][14][15] ELMO1 has also been reported to inhibit ubiqitinylation of Dock180 and so prevent its degradation by proteasomes.[16]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.[17] In tumour cells DOCK180 is regulated by a complex containing Crk and p130Cas which is in turn regulated by cooperative signalling by β3-containingintegrin complexes and the membrane-bound protein uPAR.[18]
^ a b cGRCh38: Ensembl release 89: ENSG00000150760 – Ensembl, May 2017
^ a b cGRCm38: Ensembl release 89: ENSMUSG00000058325 – Ensembl, May 2017
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^Hasegawa H, Kiyokawa E, Tanaka S, et al. (April 1996). "DOCK180, a major CRK-binding protein, alters cell morphology upon translocation to the cell membrane". Mol. Cell. Biol. 16 (4): 1770–76. doi:10.1128/mcb.16.4.1770. PMC231163. PMID 8657152.
^Kiyokawa E, Hashimoto Y, Kobayashi S, et al. (November 1998). "Activation of Rac1 by a Crk SH3-binding protein, DOCK180". Genes Dev. 12 (21): 3331–36. doi:10.1101/gad.12.21.3331. PMC317231. PMID 9808620.
^ a bCôté JF, Vuori K (December 2002). "Identification of an evolutionarily conserved superfamily of DOCK180-related proteins with guanine nucleotide exchange activity". J. Cell Sci. 115 (Pt 24): 4901–13. doi:10.1242/jcs.00219. PMID 12432077. S2CID 14669715.
^Côté JF, Motoyama AB, Bush JA, et al. (August 2005). "A novel and evolutionarily conserved PtdIns(3,4,5)P3-binding domain is necessary for DOCK180 signaling". Nat. Cell Biol. 7 (8): 797–807. doi:10.1038/ncb1280. PMC1352170. PMID 16025104.
^ a bBrugnera E, Haney L, Grimsley C, et al. (August 2002). "Unconventional Rac-GEF activity is mediated through the Dock180-ELMO complex". Nat. Cell Biol. 4 (8): 574–82. doi:10.1038/ncb824. PMID 12134158. S2CID 36363774.
^Balagopalan L, Chen MH, Geisbrecht ER, et al. (December 2006). "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. doi:10.1128/MCB.00016-06. PMC1698515. PMID 17030600.
^Lu M, Ravichandran KS (2006). "Dock180–ELMO Cooperation in Rac Activation". Regulators and Effectors of Small GTPases: Rho Family. Methods in Enzymology. Vol. 406. pp. 388–402. doi:10.1016/S0076-6879(06)06028-9. ISBN978-0-12-182811-0. PMID 16472672. {{cite book}}: |journal= ignored (help)
^Lu M, Kinchen JM, Rossman KL, et al. (2004). "PH domain of ELMO functions in trans to regulate Rac activation via Dock180". Nature Structural & Molecular Biology. 11 (8): 756–62. doi:10.1038/nsmb800. PMID 15247908. S2CID 125990.
^Lu M, Kinchen JM, Rossman KL, et al. (February 2005). "A Steric-inhibition model for regulation of nucleotide exchange via the Dock180 family of GEFs". Curr. Biol. 15 (4): 371–77. Bibcode:2005CBio...15..371L. doi:10.1016/j.cub.2005.01.050. PMID 15723800. S2CID 14267018.
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^Smith HW, Marra P, Marshall CJ (August 2008). "uPAR promotes formation of the p130Cas–Crk complex to activate Rac through DOCK180". J. Cell Biol. 182 (4): 777–90. doi:10.1083/jcb.200712050. PMC2518715. PMID 18725541.
^Gumienny TL, Brugnera E, Tosello-Trampont AC, et al. (October 2001). "CED-12/ELMO, a novel member of the CrkII/Dock180/Rac pathway, is required for phagocytosis and cell migration" (PDF). Cell. 107 (1): 27–41. doi:10.1016/S0092-8674(01)00520-7. PMID 11595183. S2CID 15232864. Archived from the original (PDF) on 2021-09-22. Retrieved 2020-09-13.
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^Moore CA, Parkin CA, Bidet Y, et al. (September 2007). "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. doi:10.1242/dev.001214. PMID 17670792.
^Hara S, Kiyokawa E, Iemura SI, et al. (July 2008). "The DHR1 Domain of DOCK180 Binds to SNX5 and Regulates Cation-independent Mannose 6-phosphate Receptor Transport". Mol. Biol. Cell. 19 (9): 3823–35. doi:10.1091/mbc.E08-03-0314. PMC2526700. PMID 18596235.
^Jarzynka MJ, Hu B, Hui KM, et al. (August 2007). "ELMO1 and Dock180, a Bipartite Rac1 Guanine Nucleotide Exchange Factor, Promote Human Glioma Cell Invasion". Cancer Res. 67 (15): 7203–11. doi:10.1158/0008-5472.CAN-07-0473. PMC2867339. PMID 17671188.
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^ a bHasegawa H, Kiyokawa E, Tanaka S, Nagashima K, Gotoh N, Shibuya M, Kurata T, Matsuda M (Apr 1996). "DOCK180, a major CRK-binding protein, alters cell morphology upon translocation to the cell membrane". Mol. Cell. Biol. 16 (4): 1770–6. doi:10.1128/MCB.16.4.1770. PMC231163. PMID 8657152.
^Nishihara H, Kobayashi S, Hashimoto Y, Ohba F, Mochizuki N, Kurata T, Nagashima K, Matsuda M (Nov 1999). "Non-adherent cell-specific expression of DOCK2, a member of the human CDM-family proteins". Biochim. Biophys. Acta. 1452 (2): 179–87. doi:10.1016/s0167-4889(99)00133-0. PMID 10559471.
^Gu J, Sumida Y, Sanzen N, Sekiguchi K (Jul 2001). "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. doi:10.1074/jbc.M102284200. PMID 11369773.
^Matsuda M, Ota S, Tanimura R, Nakamura H, Matuoka K, Takenawa T, Nagashima K, Kurata T (Jun 1996). "Interaction between the amino-terminal SH3 domain of CRK and its natural target proteins". J. Biol. Chem. 271 (24): 14468–72. doi:10.1074/jbc.271.24.14468. PMID 8662907.
^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 (Oct 2001). "CED-12/ELMO, a novel member of the CrkII/Dock180/Rac pathway, is required for phagocytosis and cell migration" (PDF). Cell. 107 (1): 27–41. doi:10.1016/s0092-8674(01)00520-7. PMID 11595183. S2CID 15232864. Archived from the original (PDF) on 2021-09-22. Retrieved 2020-09-13.
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Further reading
Takai S, Hasegawa H, Kiyokawa E, et al. (1996). "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. doi:10.1006/geno.1996.0378. PMID 8661160.
Côté JF, Vuori K (2007). "GEF what? Dock180 and related proteins help Rac to polarize cells in new ways". Trends Cell Biol. 17 (8): 383–93. doi:10.1016/j.tcb.2007.05.001. PMC2887429. PMID 17765544.
Komander D, Patel M, Laurin M, et al. (2008). "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. doi:10.1091/mbc.E08-04-0345. PMC2575150. PMID 18768751.
Henson PM (2005). "Engulfment: ingestion and migration with Rac, Rho and TRIO". Curr. Biol. 15 (1): R29–30. Bibcode:2005CBio...15..R29H. doi:10.1016/j.cub.2004.12.017. PMID 15649349.
deBakker CD, Haney LB, Kinchen JM, et al. (2004). "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. Bibcode:2004CBio...14.2208D. doi:10.1016/j.cub.2004.12.029. PMID 15620647. S2CID 1269946.
Yin J, Haney L, Walk S, et al. (2004). "Nuclear localization of the DOCK180/ELMO complex". Arch. Biochem. Biophys. 429 (1): 23–29. doi:10.1016/j.abb.2004.05.014. PMID 15288806.
Matsuda M, Ota S, Tanimura R, et al. (1996). "Interaction between the amino-terminal SH3 domain of CRK and its natural target proteins". J. Biol. Chem. 271 (24): 14468–72. doi:10.1074/jbc.271.24.14468. PMID 8662907.
Wu YC, Horvitz HR (1998). "C. elegans phagocytosis and cell-migration protein CED-5 is similar to human DOCK180". Nature. 392 (6675): 501–4. Bibcode:1998Natur.392..501W. doi:10.1038/33163. PMID 9548255. S2CID 205002377.
Albert ML, Kim JI, Birge RB (2001). "alphavbeta5 integrin recruits the CrkII-Dock180-rac1 complex for phagocytosis of apoptotic cells". Nat. Cell Biol. 2 (12): 899–905. doi:10.1038/35046549. PMID 11146654. S2CID 7535200.
Kobayashi S, Shirai T, Kiyokawa E, et al. (2001). "Membrane recruitment of DOCK180 by binding to PtdIns(3,4,5)P3". Biochem. J. 354 (Pt 1): 73–8. doi:10.1042/0264-6021:3540073. PMC1221630. PMID 11171081.
Tu Y, Kucik DF, Wu C (2001). "Identification and kinetic analysis of the interaction between Nck-2 and DOCK180". FEBS Lett. 491 (3): 193–9. doi:10.1016/S0014-5793(01)02195-0. PMID 11240126. S2CID 31372015.
Gu J, Sumida Y, Sanzen N, Sekiguchi K (2001). "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. doi:10.1074/jbc.M102284200. PMID 11369773.
Zhou Z, Caron E, Hartwieg E, et al. (2001). "The C. elegans PH domain protein CED-12 regulates cytoskeletal reorganization via a Rho/Rac GTPase signaling pathway". Dev. Cell. 1 (4): 477–89. doi:10.1016/S1534-5807(01)00058-2. PMID 11703939.
Grimsley CM, Kinchen JM, Tosello-Trampont AC, et al. (2004). "Dock180 and ELMO1 proteins cooperate to promote evolutionarily conserved Rac-dependent cell migration". J. Biol. Chem. 279 (7): 6087–97. doi:10.1074/jbc.M307087200. PMID 14638695. S2CID 2324987.
Wang X, Wu YC, Fadok VA, et al. (2003). "Cell corpse engulfment mediated by C. elegans phosphatidylserine receptor through CED-5 and CED-12" (PDF). Science. 302 (5650): 1563–6. Bibcode:2003Sci...302.1563W. doi:10.1126/science.1087641. PMID 14645848. S2CID 25672278.