DOCK1

DOCK1（Dedicator of cytokinesis 的首字母縮寫，因其分子量較大，約180kDa，也被稱為Dock180）是哺乳動物的一種涉及細胞內信號網絡轉導的蛋白^[5]，屬於鳥苷酸交換因子（英語：Guanine nucleotide exchange factor）（Guanine nucleotide exchange factors，GEFs）中的DOCK蛋白家族，其在線蟲（C. elegans）中的同源基因為CED-5^[6]，果蠅（D. melanogaster）中的同源物為Mbc（Myoblast city）。

DOCK1
已知的結構 PDB 直系同源搜尋: PDBe RCSB PDBID列表 3L4C
識別號
別名	DOCK1；, DOCK180, ced5, Dock180, dedicator of cytokinesis 1
外部ID	OMIM：601403 MGI：2429765 HomoloGene：55575 GeneCards：DOCK1
基因位置（人類） 染色體 10號染色體[1] 基因座 10q26.2 起始 126,905,409 bp[1] 終止 127,452,517 bp[1]
基因位置（小鼠） 染色體 小鼠7號染色體[2] 基因座 7|7 F3 起始 134,272,383 bp[2] 終止 134,775,368 bp[2]
基因本體 分子功能 • GTPase activator activity • guanyl-nucleotide exchange factor activity • SH3 domain binding • 血漿蛋白結合 細胞組分 • 膜 • guanyl-nucleotide exchange factor complex • 細胞質 • 細胞核 • 細胞質基質 • nuclear speck 生物學過程 • Fc-gamma receptor signaling pathway involved in phagocytosis • small GTPase mediated signal transduction • 凝血 • phagocytosis, engulfment • vascular endothelial growth factor receptor signaling pathway • 細胞骨架組織 • 吞噬作用 • integrin-mediated signaling pathway • 細胞遷移 • 信號轉導 • 細胞凋亡 • positive regulation of GTPase activity • positive regulation of epithelial cell migration • positive regulation of substrate adhesion-dependent cell spreading Sources:Amigo / QuickGO
直系同源
物種	人類	小鼠
Entrez	1793	330662
Ensembl	ENSG00000150760	ENSMUSG00000058325
UniProt	Q14185	Q8BUR4
mRNA​序列	NM_001290223 ​NM_001380	NM_001033420
蛋白序列	NP_001277152 ​NP_001371 ​NP_001364472 ​NP_001364473 ​NP_001364475 ​NP_001364476 ​NP_001364477 ​NP_001364479 ​NP_001364482 ​NP_001364483 ​NP_001364485 ​NP_001364487 ​NP_001364489 ​NP_001364490	NP_001028592
基因位置​（UCSC）	Chr 10: 126.91 – 127.45 Mb	Chr 7: 134.27 – 134.78 Mb
PubMed​查找	[3]	[4]
維基數據
檢視/編輯人類 檢視/編輯小鼠

發現

1996年，Dock1在銜接蛋白Crk（英語：CRK (gene)）的FWB實驗（英語：far-western blotting）結合蛋白中發現，可誘導3T3纖維母細胞發生形態學改變^[7]。1998年發現Dock1可活化Rac1（英語：Rac1）（一種小G蛋白（英語：Small GTPase））^[8]，2002年確定了Dock1是一種鳥苷酸交換因子（GEF）^[9]。

結構和功能

Dock1是一種鳥苷酸交換因子（GEFs），在細胞信號轉導中參與活化小G蛋白。G蛋白在與二磷酸鳥苷（GDP）結合時為靜息的狀態，與三磷酸鳥苷（GTP）結合時為活化狀態，GEF通過打開G蛋白的鳥苷酸結合位置，將GDP置換為GTP來使G蛋白活化。

和其它GEFs通過經典的串聯DH（英語：DH domain）-PH結構域來執行鳥苷酸交換不同，Dock1及相關蛋白通過DHR2結構域（英語：DHR2 domain）來活化Rac1，DHR2結構域能穩定Rac的無核苷酸狀態^[9]。Dock1及相關蛋白的另一個結構域DHR1（英語：DHR1 domain）可在體外（in vitro）結合磷脂^[10]，可能和DOCK與細胞膜的相互作用有關。Dock1還包括N-末端的SH3結構域（用於結合ELMO蛋白）^[11]，C-末端的富脯氨酸區域（果蠅Mbc的這一區域能結合Crk（英語：CRK (gene)）的果蠅同源物DCrk）^[12]。

Dock1的活性調節

在正常的生理條件下，單獨存在的Dock1是不會交換活化Rac的^[11]。Dock1需要與其伴侶蛋白ELMO相互作用來啟動GEF活性。ELMO1（英語：ELMO1）將Dock1招募到質膜上並改變其構象增加GEF活性^[13][14][15]。ELMO1也抑制了Dock1的泛素化，使之不被蛋白酶體降解^[16]。受體介導的RhoG（小G蛋白Rac亞家族（英語：Rac (GTPase)）的成員之一）活化能誘導Dock1產生GEF活性。活化的（GTP結合的）RhoG能招募ELMO/Dock1複合物到質膜上，參與其它Rac蛋白的鳥苷酸交換^[17]。在腫瘤細胞中，帶有β₃亞基的整合素異二聚體和膜結合蛋白尿激酶受體共同信號刺激下Crk和p130Cas（英語：BCAR1）複合體調控Dock1^[18]。

Dock1的下游信號

Dock1是一種Rac特異性的GEF，其活化能導致Rac下游信號的活化及一系列細胞功能，包括線蟲凋亡細胞的細胞遷移和吞噬作用^[19]，PC12細胞的神經突生長^[20]和斑馬魚胚胎中的肌細胞融合^[21]。2008年的一項研究發現Dock1的DHR1結構域可結合SNX5（一種分選蛋白），這一相互作用促使了胰島素樣生長因子2受體跨高爾基體網絡的逆向轉運，此信號途徑不經過Rac蛋白^[22]。此外，Dock1和Elmo基因表達的增加能提高神經膠質瘤的侵襲性^[23]。

相互作用

Dock1可與下列蛋白發生交互作用：

• BCAR1^[24]
• CRK^{[24][25][26][27][28]}
• ELMO1^[29][30]
• Grb2^[24][25]

參考文獻

1. GRCh38: Ensembl release 89: ENSG00000150760 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000058325 - Ensembl, May 2017
3. Human PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.
4. Mouse PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Entrez Gene: DOCK1 dedicator of cytokinesis 1. （原始內容存檔於2010-12-05）.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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 .
15. 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.
16. 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.
17. 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.
18. 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.
19. 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.
20. 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.
21. 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 .
22. 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.
23. 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.
24. 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.
25. 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.
26. 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.
27. 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.
28. 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.
29. 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.
30. 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.

延伸閱讀

• 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. （原始內容存檔 (PDF)於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.

外部連結

• 醫學主題詞表（MeSH）：DOCK1+protein,+human
• DOCK180 Info with links in the Cell Migration Gateway
• PDB中UniProt可用的所有結構資訊之概述：Q14185 (Dedicator of cytokinesis protein 1) 在PDBe-KB（英語：PDBe-KB）。