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==Regulation of Dock180 Activity==
==Regulation of Dock180 Activity==
Under physiological conditions Dock180 alone is inefficient at promoting nucleotide exchange on Rac.<ref name="Brugnera_2002"/> Effective GEF activity requires an interaction between Dock180 and its binding partner [[ELMO (protein)|ELMO]]. [[ELMO1]] is the most comprehensively described [[isoform]] of this small family of non-[[Biocatalysis|catalytically]] active proteins which function to recruit Dock180 to the [[plasma membrane]] and induce conformational changes which increase GEF efficiency.<ref name="Lu_2006">{{cite journal | vauthors = Lu M, Ravichandran KS | title = Dock180-ELMO cooperation in Rac activation| journal = Meth. Enzym. | volume = 406 | issue = | pages = 388–402 | year = 2006 | pmid = 16472672  | doi = 10.1016/S0076-6879(06)06028-9| url =  }}</ref><ref name="Lu_2004">{{cite journal | vauthors = Lu M, Kinchen JM, Rossman KL | title = PH domain of ELMO functions ''in trans'' to regulate Rac activation via Dock180| journal = Nature Structural & Molecular Biology | volume = 11 | issue = 8 | pages = 756–62 | year = 2004 | pmid = 15247908 | doi = 10.1038/nsmb800| url =  |display-authors=etal}}</ref><ref name="Lu_2005">{{cite journal | vauthors = Lu M, Kinchen JM, Rossman KL | title = A Steric-inhibition model for regulation of nucleotide exchange via the Dock180 family of GEFs| journal = Curr. Biol. | volume = 15 | issue = 4 | pages = 371–77 |date=February 2005 | pmid = 15723800 | doi = 10.1016/j.cub.2005.01.050| url =  |display-authors=etal}}</ref> ELMO1 has also been reported to inhibit [[Ubiquitin|ubiqitinylation]] of Dock180 and so prevent its degradation by [[proteasomes]].<ref name="Makino_2006">{{cite journal | vauthors = Makino Y, Tsuda M, Ichihara S | title = Elmo1 inhibits ubiquitylation of Dock180| journal = J. Cell Sci. | volume = 119 | issue = Pt 5 | pages = 923–32 |date=March 2006 | pmid = 16495483 | doi = 10.1242/jcs.02797| url =  |display-authors=etal}}</ref> [[Receptor (biochemistry)|Receptor]]-mediated activation of [[RhoG]] (a small G protein of the [[Rac (GTPase)|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 (biochemistry)|substrate]], Rac.<ref name="Katoh_2003">{{cite journal | vauthors = Katoh H, Negishi M| title = RhoG activates Rac1 by direct interaction with the Dock180-binding protein Elmo| journal = Nature | volume = 424 | issue = 6947 | pages = 461–64 |date=July 2003 | pmid = 12879077 | doi = 10.1038/nature01817| url =  }}</ref> In [[tumour]] cells Dock180 is regulated by a complex containing Crk and [[p130Cas]] which is in turn regulated by cooperative signalling by β<sub>3</sub>-containing [[integrin]] complexes and the membrane-bound protein [[uPAR]].<ref name="Smith_2008">{{cite journal | vauthors = Smith HW, Marra P, Marshall CJ| title = uPAR promotes formation of the p130Cas–Crk complex to activate Rac through DOCK180| journal = J. Cell Biol. | volume = 182 | issue = 4 | pages = 777–90 |date=August 2008 | pmid = 18725541 | doi = 10.1083/jcb.200712050| url = | pmc = 2518715  }}</ref>
Under physiological conditions Dock180 alone is inefficient at promoting nucleotide exchange on Rac.<ref name="Brugnera_2002"/> Effective GEF activity requires an interaction between Dock180 and its binding partner [[ELMO (protein)|ELMO]]. [[ELMO1]] is the most comprehensively described [[isoform]] of this small family of non-[[Biocatalysis|catalytically]] active proteins which function to recruit Dock180 to the [[plasma membrane]] and induce conformational changes which increase GEF efficiency.<ref name="Lu_2006">{{cite journal | vauthors = Lu M, Ravichandran KS | title = Dock180-ELMO cooperation in Rac activation| journal = Meth. Enzymol. | volume = 406 | issue = | pages = 388–402 | year = 2006 | pmid = 16472672  | doi = 10.1016/S0076-6879(06)06028-9| url =  }}</ref><ref name="Lu_2004">{{cite journal | vauthors = Lu M, Kinchen JM, Rossman KL | title = PH domain of ELMO functions ''in trans'' to regulate Rac activation via Dock180| journal = Nature Structural & Molecular Biology | volume = 11 | issue = 8 | pages = 756–62 | year = 2004 | pmid = 15247908 | doi = 10.1038/nsmb800| url =  |display-authors=etal}}</ref><ref name="Lu_2005">{{cite journal | vauthors = Lu M, Kinchen JM, Rossman KL | title = A Steric-inhibition model for regulation of nucleotide exchange via the Dock180 family of GEFs| journal = Curr. Biol. | volume = 15 | issue = 4 | pages = 371–77 |date=February 2005 | pmid = 15723800 | doi = 10.1016/j.cub.2005.01.050| url =  |display-authors=etal}}</ref> ELMO1 has also been reported to inhibit [[Ubiquitin|ubiqitinylation]] of Dock180 and so prevent its degradation by [[proteasomes]].<ref name="Makino_2006">{{cite journal | vauthors = Makino Y, Tsuda M, Ichihara S | title = Elmo1 inhibits ubiquitylation of Dock180| journal = J. Cell Sci. | volume = 119 | issue = Pt 5 | pages = 923–32 |date=March 2006 | pmid = 16495483 | doi = 10.1242/jcs.02797| url =  |display-authors=etal}}</ref> [[Receptor (biochemistry)|Receptor]]-mediated activation of [[RhoG]] (a small G protein of the [[Rac (GTPase)|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 (biochemistry)|substrate]], Rac.<ref name="Katoh_2003">{{cite journal | vauthors = Katoh H, Negishi M| title = RhoG activates Rac1 by direct interaction with the Dock180-binding protein Elmo| journal = Nature | volume = 424 | issue = 6947 | pages = 461–64 |date=July 2003 | pmid = 12879077 | doi = 10.1038/nature01817| url =  }}</ref> In [[tumour]] cells Dock180 is regulated by a complex containing Crk and [[p130Cas]] which is in turn regulated by cooperative signalling by β<sub>3</sub>-containing [[integrin]] complexes and the membrane-bound protein [[uPAR]].<ref name="Smith_2008">{{cite journal | vauthors = Smith HW, Marra P, Marshall CJ| title = uPAR promotes formation of the p130Cas–Crk complex to activate Rac through DOCK180| journal = J. Cell Biol. | volume = 182 | issue = 4 | pages = 777–90 |date=August 2008 | pmid = 18725541 | doi = 10.1083/jcb.200712050| url = | pmc = 2518715  }}</ref>


==Signalling Downstream of Dock180==
==Signalling Downstream of Dock180==

Latest revision as of 18:34, 29 April 2018

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Dock180, (Dedicator of cytokinesis) also known as DOCK1, is a large (~180 kDa) protein 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 ubiqitinylation 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:

References

  1. ↑ "Entrez Gene: DOCK1 dedicator of cytokinesis 1".
  2. ↑ Meller N, Merlot S, Guda C (November 2005). "CZH proteins: a new family of Rho-GEFs". J. Cell Sci. 118 (Pt 21): 4937–46. doi:10.1242/jcs.02671. PMID 16254241.
  3. ↑ 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. PMC 231163. PMID 8657152.
  4. ↑ 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. PMC 317231. PMID 9808620.
  5. ↑ 5.0 5.1 Côté 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.
  6. ↑ 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. PMC 1352170. PMID 16025104.
  7. ↑ 7.0 7.1 Brugnera 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.
  8. ↑ 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. PMC 1698515. PMID 17030600.
  9. ↑ Lu M, Ravichandran KS (2006). "Dock180-ELMO cooperation in Rac activation". Meth. Enzymol. 406: 388–402. doi:10.1016/S0076-6879(06)06028-9. PMID 16472672.
  10. ↑ 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.
  11. ↑ 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. doi:10.1016/j.cub.2005.01.050. PMID 15723800.
  12. ↑ Makino Y, Tsuda M, Ichihara S, et al. (March 2006). "Elmo1 inhibits ubiquitylation of Dock180". J. Cell Sci. 119 (Pt 5): 923–32. doi:10.1242/jcs.02797. PMID 16495483.
  13. ↑ Katoh H, Negishi M (July 2003). "RhoG activates Rac1 by direct interaction with the Dock180-binding protein Elmo". Nature. 424 (6947): 461–64. doi:10.1038/nature01817. PMID 12879077.
  14. ↑ 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. PMC 2518715. PMID 18725541.
  15. ↑ 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". Cell. 107 (1): 27–41. doi:10.1016/S0092-8674(01)00520-7. PMID 11595183.
  16. ↑ Katoh H, Yasui H, Yamaguchi Y, et al. (October 2000). "Small GTPase RhoG Is a Key Regulator for Neurite Outgrowth in PC12 Cells". Mol. Cell. Biol. 20 (19): 7378–87. doi:10.1128/MCB.20.19.7378-7387.2000. PMC 86291. PMID 10982854.
  17. ↑ 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.
  18. ↑ 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. PMC 2526700. PMID 18596235.
  19. ↑ 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. PMC 2867339. PMID 17671188.
  20. ↑ 20.0 20.1 20.2 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 (Mar 2003). "Differential regulation of cell motility and invasion by FAK". J. Cell Biol. 160 (5): 753–67. doi:10.1083/jcb.200212114. PMC 2173366. PMID 12615911.
  21. ↑ 21.0 21.1 Hasegawa 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. PMC 231163. PMID 8657152.
  22. ↑ 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.
  23. ↑ 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.
  24. ↑ 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.
  25. ↑ 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". Cell. 107 (1): 27–41. doi:10.1016/s0092-8674(01)00520-7. PMID 11595183.
  26. ↑ Brugnera E, Haney L, Grimsley C, Lu M, Walk SF, Tosello-Trampont AC, Macara IG, Madhani H, Fink GR, Ravichandran KS (Aug 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.

Further reading

External links


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