DOCK1

DOCK1（Dedicator of cytokinesis 的首字母缩写，因其分子量较大，约180kDa，也被称为Dock180）是哺乳动物的一种涉及细胞内信号网络转导的蛋白，属于鸟苷酸交换因子（英语：Guanine nucleotide exchange factor）（Guanine nucleotide exchange factors，GEFs）中的DOCK蛋白家族，其在线虫（C. elegans）中的同源基因为CED-5，果蝇（D. melanogaster）中的同源物为Mbc（Myoblast city）。 1996年，Dock1在衔接蛋白Crk（英语：CRK (gene)）的FWB实验（英语：far-western blotting）结合蛋白中发现，可诱导3T3成纤维细胞发生形态学改变。1998年发现Dock1可激活Rac1（英语：Rac1）（一种小G蛋白（英语：Small GTPase）），2002年确定了Dock1是一种鸟苷酸交换因子（GEF）。 Dock1是一种鸟苷酸交换因子（GEFs），在细胞信号转导中参与激活小G蛋白。G蛋白在与二磷酸鸟苷（GDP）结合时为静息的状态，与三磷酸鸟苷（GTP）结合时为激活状态，GEF通过打开G蛋白的鸟苷酸结合位置，将GDP置换为GTP来使G蛋白激活。 和其它GEFs通过经典的串联DH（英语：DH domain）-PH结构域来执行鸟苷酸交换不同，Dock1及相关蛋白通过DHR2结构域（英语：DHR2 domain）来激活Rac1，DHR2结构域能稳定Rac的无核苷酸状态。Dock1及相关蛋白的另一个结构域DHR1（英语：DHR1 domain）可在体外（in vitro）结合磷脂，可能和DOCK与细胞膜的相互作用有关。Dock1还包括N-末端的SH3结构域（用于结合ELMO蛋白），C-末端的富脯氨酸区域（果蝇Mbc的这一区域能结合Crk（英语：CRK (gene)）的果蝇同源物DCrk）。 在正常的生理条件下，单独存在的Dock1是不会交换激活Rac的。Dock1需要与其伴侣蛋白ELMO相互作用来启动GEF活性。ELMO1（英语：ELMO1）将Dock1招募到质膜上并改变其构象增加GEF活性。ELMO1也抑制了Dock1的泛素化，使之不被蛋白酶体降解。受体介导的RhoG（小G蛋白Rac亚家族（英语：Rac (GTPase)）的成员之一）激活能诱导Dock1产生GEF活性。激活的（GTP结合的）RhoG能招募ELMO/Dock1复合物到质膜上，参与其它Rac蛋白的鸟苷酸交换。在肿瘤细胞中，带有β3亚基的整合素异二聚体和膜结合蛋白尿激酶受体共同信号刺激下Crk和p130Cas（英语：BCAR1）复合体调控Dock1。 Dock1是一种Rac特异性的GEF，其激活能导致Rac下游信号的激活及一系列细胞功能，包括线虫凋亡细胞的细胞迁移和吞噬作用，PC12细胞的神经突生长和斑马鱼胚胎中的肌细胞融合。2008年的一项研究发现Dock1的DHR1结构域可结合SNX5（一种分选蛋白），这一相互作用促使了胰岛素样生长因子2受体跨高尔基体网络的逆向转运，此信号途径不经过Rac蛋白。此外，Dock1和Elmo基因表現的增加能提高神經膠質瘤的侵袭性。 Dock1可与下列蛋白发生交互作用： BCAR1 CRK ELMO1 Grb2 GRCh38: Ensembl release 89: ENSG00000150760 - Ensembl, May 2017 GRCm38: Ensembl release 89: ENSMUSG00000058325 - Ensembl, May 2017 Human PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.  Mouse PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.  Entrez Gene: DOCK1 dedicator of cytokinesis 1. （原始内容存档于2010-12-05）.  Meller N, Merlot S, Guda C. CZH proteins: a new family of Rho-GEFs. J. Cell Sci. November 2005, 118 (Pt 21): 4937–46. PMID 16254241. doi:10.1242/jcs.02671.  Hasegawa H, Kiyokawa E, Tanaka S, et al. DOCK180, a major CRK-binding protein, alters cell morphology upon translocation to the cell membrane. Mol. Cell. Biol. April 1996, 16 (4): 1770–76. PMC 231163 . PMID 8657152. doi:10.1128/mcb.16.4.1770.  Kiyokawa E, Hashimoto Y, Kobayashi S, et al. Activation of Rac1 by a Crk SH3-binding protein, DOCK180. Genes Dev. November 1998, 12 (21): 3331–36. PMC 317231 . PMID 9808620. doi:10.1101/gad.12.21.3331.  Côté JF, Vuori K. Identification of an evolutionarily conserved superfamily of DOCK180-related proteins with guanine nucleotide exchange activity. J. Cell Sci. December 2002, 115 (Pt 24): 4901–13. PMID 12432077. doi:10.1242/jcs.00219.  Côté JF, Motoyama AB, Bush JA, et al. A novel and evolutionarily conserved PtdIns(3,4,5)P3-binding domain is necessary for DOCK180 signaling. Nat. Cell Biol. August 2005, 7 (8): 797–807. PMC 1352170 . PMID 16025104. doi:10.1038/ncb1280.  Brugnera E, Haney L, Grimsley C, et al. Unconventional Rac-GEF activity is mediated through the Dock180-ELMO complex. Nat. Cell Biol. August 2002, 4 (8): 574–82. PMID 12134158. doi:10.1038/ncb824.  Balagopalan L, Chen MH, Geisbrecht ER, et al. 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. December 2006, 26 (24): 9442–55. PMC 1698515 . PMID 17030600. doi:10.1128/MCB.00016-06.  Lu M, Ravichandran KS. Dock180-ELMO cooperation in Rac activation. Meth. Enzymol. Methods in Enzymology. 2006, 406: 388–402. ISBN 9780121828110. PMID 16472672. doi:10.1016/S0076-6879(06)06028-9.  Lu M, Kinchen JM, Rossman KL, et al. PH domain of ELMO functions in trans to regulate Rac activation via Dock180. Nature Structural & Molecular Biology. 2004, 11 (8): 756–62. PMID 15247908. doi:10.1038/nsmb800 .  Lu M, Kinchen JM, Rossman KL, et al. A Steric-inhibition model for regulation of nucleotide exchange via the Dock180 family of GEFs. Curr. Biol. 2005-02, 15 (4): 371–377. PMID 15723800. doi:10.1016/j.cub.2005.01.050.  Makino Y, Tsuda M, Ichihara S, et al. Elmo1 inhibits ubiquitylation of Dock180. J. Cell Sci. 2006-03, 119 (Pt 5): 923–932. PMID 16495483. doi:10.1242/jcs.02797.  Katoh H, Negishi M. RhoG activates Rac1 by direct interaction with the Dock180-binding protein Elmo. Nature. July 2003, 424 (6947): 461–64. PMID 12879077. doi:10.1038/nature01817.  Smith HW, Marra P, Marshall CJ. uPAR promotes formation of the p130Cas–Crk complex to activate Rac through DOCK180. J. Cell Biol. 2008-08, 182 (4): 777–790. PMC 2518715 . PMID 18725541. doi:10.1083/jcb.200712050.  Gumienny TL, Brugnera E, Tosello-Trampont AC, et al. CED-12/ELMO, a novel member of the CrkII/Dock180/Rac pathway, is required for phagocytosis and cell migration. Cell. 2001-10, 107 (1): 27–41. PMID 11595183. doi:10.1016/S0092-8674(01)00520-7.  Katoh H, Yasui H, Yamaguchi Y, et al. Small GTPase RhoG Is a Key Regulator for Neurite Outgrowth in PC12 Cells. Mol. Cell. Biol. 2000-10, 20 (19): 7378–7387. PMC 86291 . PMID 10982854. doi:10.1128/MCB.20.19.7378-7387.2000.  Moore CA, Parkin CA, Bidet Y, et al. A role for the Myoblast city homologues Dock1 and Dock5 and the adaptor proteins Crk and Crk-like in zebrafish myoblast fusion. Development. 2007-09, 134 (17): 3145–3153. PMID 17670792. doi:10.1242/dev.001214 .  Hara S, Kiyokawa E, Iemura SI, et al. The DHR1 Domain of DOCK180 Binds to SNX5 and Regulates Cation-independent Mannose 6-phosphate Receptor Transport. Mol. Biol. Cell. 2008-07, 19 (9): 3823–3835. PMC 2526700 . PMID 18596235. doi:10.1091/mbc.E08-03-0314.  Jarzynka MJ, Hu B, Hui KM, et al. ELMO1 and Dock180, a Bipartite Rac1 Guanine Nucleotide Exchange Factor, Promote Human Glioma Cell Invasion. Cancer Res. 2007-08, 67 (15): 7203–11. PMC 2867339 . PMID 17671188. doi:10.1158/0008-5472.CAN-07-0473.  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. Mar 2003, 160 (5): 753–67. PMC 2173366 . PMID 12615911. doi:10.1083/jcb.200212114.  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. Apr 1996, 16 (4): 1770–6. PMC 231163 . PMID 8657152. doi:10.1128/MCB.16.4.1770.  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. Nov 1999, 1452 (2): 179–87. PMID 10559471. doi:10.1016/s0167-4889(99)00133-0.  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. Jul 2001, 276 (29): 27090–7. PMID 11369773. doi:10.1074/jbc.M102284200.  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. Jun 1996, 271 (24): 14468–72. PMID 8662907. doi:10.1074/jbc.271.24.14468.  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. Oct 2001, 107 (1): 27–41. PMID 11595183. doi:10.1016/s0092-8674(01)00520-7.  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. Aug 2002, 4 (8): 574–82. PMID 12134158. doi:10.1038/ncb824.  Takai S, Hasegawa H, Kiyokawa E, et al. Chromosomal mapping of the gene encoding DOCK180, a major Crk-binding protein, to 10q26.13-q26.3 by fluorescence in situ hybridization. Genomics. 1996, 35 (2): 403–4. PMID 8661160. doi:10.1006/geno.1996.0378.  Côté JF, Vuori K. GEF what? Dock180 and related proteins help Rac to polarize cells in new ways. Trends Cell Biol. 2007, 17 (8): 383–93. PMC 2887429 . PMID 17765544. doi:10.1016/j.tcb.2007.05.001.  Komander D, Patel M, Laurin M, et al. An α-Helical Extension of the ELMO1 Pleckstrin Homology Domain Mediates Direct Interaction to DOCK180 and Is Critical in Rac Signaling. Mol. Biol. Cell. 2008, 19 (11): 4837–51. PMC 2575150 . PMID 18768751. doi:10.1091/mbc.E08-04-0345.  Henson PM. Engulfment: ingestion and migration with Rac, Rho and TRIO. Curr. Biol. 2005, 15 (1): R29–30. PMID 15649349. doi:10.1016/j.cub.2004.12.017.  deBakker CD, Haney LB, Kinchen JM, et al. 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. 2004, 14 (24): 2208–16. PMID 15620647. doi:10.1016/j.cub.2004.12.029.  Yin J, Haney L, Walk S, et al. Nuclear localization of the DOCK180/ELMO complex. Arch. Biochem. Biophys. 2004, 429 (1): 23–29. PMID 15288806. doi:10.1016/j.abb.2004.05.014.  Matsuda M, Ota S, Tanimura R, et al. Interaction between the amino-terminal SH3 domain of CRK and its natural target proteins. J. Biol. Chem. 1996, 271 (24): 14468–72. PMID 8662907. doi:10.1074/jbc.271.24.14468.  Savill J. Apoptosis. Phagocytic docking without shocking. Nature. 1998, 392 (6675): 442–3. PMID 9548247. doi:10.1038/33025.  Wu YC, Horvitz HR. C. elegans phagocytosis and cell-migration protein CED-5 is similar to human DOCK180. Nature. 1998, 392 (6675): 501–4. PMID 9548255. doi:10.1038/33163.  Albert ML, Kim JI, Birge RB. alphavbeta5 integrin recruits the CrkII-Dock180-rac1 complex for phagocytosis of apoptotic cells. Nat. Cell Biol. 2001, 2 (12): 899–905. PMID 11146654. doi:10.1038/35046549.  Kobayashi S, Shirai T, Kiyokawa E, et al. Membrane recruitment of DOCK180 by binding to PtdIns(3,4,5)P3. Biochem. J. 2001, 354 (Pt 1): 73–8. PMC 1221630 . PMID 11171081. doi:10.1042/0264-6021:3540073.  Tu Y, Kucik DF, Wu C. Identification and kinetic analysis of the interaction between Nck-2 and DOCK180. FEBS Lett. 2001, 491 (3): 193–9. PMID 11240126. doi:10.1016/S0014-5793(01)02195-0.  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. 2001, 276 (29): 27090–7. PMID 11369773. doi:10.1074/jbc.M102284200.  Zhou Z, Caron E, Hartwieg E, et al. The C. elegans PH domain protein CED-12 regulates cytoskeletal reorganization via a Rho/Rac GTPase signaling pathway. Dev. Cell. 2001, 1 (4): 477–89. PMID 11703939. doi:10.1016/S1534-5807(01)00058-2.  Grimsley CM, Kinchen JM, Tosello-Trampont AC, et al. Dock180 and ELMO1 proteins cooperate to promote evolutionarily conserved Rac-dependent cell migration (PDF). J. Biol. Chem. 2004, 279 (7): 6087–97 [2020-04-23]. PMID 14638695. doi:10.1074/jbc.M307087200. （原始内容存档 (PDF)于2017-07-05）.  Wang X, Wu YC, Fadok VA, et al. Cell corpse engulfment mediated by C. elegans phosphatidylserine receptor through CED-5 and CED-12. Science. 2003, 302 (5650): 1563–6. PMID 14645848. doi:10.1126/science.1087641.  醫學主題詞表（MeSH）：DOCK1+protein,+human DOCK180 Info with links in the Cell Migration Gateway PDB中UniProt可用的所有結構信息之概述：Q14185 (Dedicator of cytokinesis protein 1) 在PDBe-KB（英语：PDBe-KB）。