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{{Short description|Protein found in humans}}
{{cs1 config|name-list-style=vanc}}
{{Infobox_gene}}
{{Infobox_gene}}
'''Dock180''', (<u>D</u>edicator <u>o</u>f <u>c</u>yto<u>k</u>inesis) also known as '''DOCK1''', is a large (~180 kDa) [[protein]] involved in [[intracellular]] [[cell signalling|signalling networks]].<ref name="entrez">{{cite web | title = Entrez Gene: DOCK1 dedicator of cytokinesis 1| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1793| accessdate = }}</ref> It is the mammalian [[ortholog]] of the ''[[Caenorhabditis elegans|C. elegans]]'' protein [[CED-5]] and belongs to the [[DOCK (protein)|DOCK]] family of [[Guanine nucleotide exchange factors]] (GEFs).<ref name="Meller_2005">{{cite journal | vauthors = Meller N, Merlot S, Guda C | title = CZH proteins: a new family of Rho-GEFs | journal = J. Cell Sci. | volume = 118 | issue = Pt 21 | pages = 4937–46 |date=November 2005 | pmid = 16254241 | doi = 10.1242/jcs.02671| url = }}</ref>
'''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]] [[cell signalling|signalling networks]].<ref name="entrez">{{cite web | title = Entrez Gene: DOCK1 dedicator of cytokinesis 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1793}}</ref> It is the mammalian [[ortholog]] of the ''[[Caenorhabditis elegans|C. elegans]]'' protein [[CED-5]] and belongs to the [[DOCK (protein)|DOCK]] family of [[guanine nucleotide exchange factors]] (GEFs).<ref name="Meller_2005">{{cite journal | vauthors = Meller N, Merlot S, Guda C | title = CZH proteins: a new family of Rho-GEFs | journal = J. Cell Sci. | volume = 118 | issue = Pt 21 | pages = 4937–46 |date=November 2005 | pmid = 16254241 | doi = 10.1242/jcs.02671| s2cid = 3075895 | doi-access = }}</ref>


==Discovery==
==Discovery==
Dock180 was identified, using a [[far-western blotting]] approach, as a binding partner of the [[adaptor protein]] [[CRK (gene)|Crk]] that was able to induce [[morphology (biology)|morphological changes]] in [[3T3 cells|3T3 fibroblasts]].<ref name="Hasegawa_1996">{{cite journal | vauthors = Hasegawa H, Kiyokawa E, Tanaka S | title = DOCK180, a major CRK-binding protein, alters cell morphology upon translocation to the cell membrane | journal = Mol. Cell. Biol. | volume = 16 | issue = 4 | pages = 1770–76 |date=April 1996 | pmid = 8657152 | doi = | url = | pmc = 231163 |display-authors=etal}}</ref> Subsequently it was reported that Dock180 was able to activate the small GTP-binding protein ([[G protein]]) [[Rac1]]<ref name="Kiyokawa_1998">{{cite journal | vauthors = Kiyokawa E, Hashimoto Y, Kobayashi S | title = Activation of Rac1 by a Crk SH3-binding protein, DOCK180 | journal = Genes Dev. | volume = 12 | issue = 21 | pages = 3331–36 |date=November 1998 | pmid = 9808620 | doi = 10.1101/gad.12.21.3331| url = | pmc = 317231 |display-authors=etal}}</ref> and this was later shown to happen via its ability to act as a GEF.<ref name="Cote_2002">{{cite journal | vauthors = Côté JF, Vuori K | title = Identification of an evolutionarily conserved superfamily of DOCK180-related proteins with guanine nucleotide exchange activity | journal = J. Cell Sci. | volume = 115 | issue = Pt 24 | pages = 4901–13 |date=December 2002 | pmid = 12432077 | doi = 10.1242/jcs.00219| url = }}</ref>
DOCK180 was identified, using a [[far-western blotting]] approach, as a binding partner of the [[Signal transducing adaptor protein|adaptor protein]] [[CRK (gene)|Crk]] that was able to induce [[morphology (biology)|morphological changes]] in [[3T3 cells|3T3 fibroblasts]].<ref name="Hasegawa_1996">{{cite journal | vauthors = Hasegawa H, Kiyokawa E, Tanaka S | title = DOCK180, a major CRK-binding protein, alters cell morphology upon translocation to the cell membrane | journal = Mol. Cell. Biol. | volume = 16 | issue = 4 | pages = 1770–76 |date=April 1996 | pmid = 8657152 | doi = 10.1128/mcb.16.4.1770| pmc = 231163 |display-authors=etal}}</ref> Subsequently it was reported that DOCK180 was able to activate the small GTP-binding protein ([[G protein]]) [[Rac1]]<ref name="Kiyokawa_1998">{{cite journal | vauthors = Kiyokawa E, Hashimoto Y, Kobayashi S | title = Activation of Rac1 by a Crk SH3-binding protein, DOCK180 | journal = Genes Dev. | volume = 12 | issue = 21 | pages = 3331–36 |date=November 1998 | pmid = 9808620 | doi = 10.1101/gad.12.21.3331| pmc = 317231 |display-authors=etal}}</ref> and this was later shown to happen via its ability to act as a GEF.<ref name="Cote_2002">{{cite journal | vauthors = Côté JF, Vuori K | title = Identification of an evolutionarily conserved superfamily of DOCK180-related proteins with guanine nucleotide exchange activity | journal = J. Cell Sci. | volume = 115 | issue = Pt 24 | pages = 4901–13 |date=December 2002 | pmid = 12432077 | doi = 10.1242/jcs.00219| s2cid = 14669715 | doi-access = }}</ref>


==Structure and Function==
==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 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 domain|DH]]-[[PH domain|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.<ref name="Cote_2002"/> Dock180-related proteins also possess a [[DHR1 domain]] which has been shown, ''[[in vitro]]'', to bind [[phospholipids]]<ref name="Cote_2005">{{cite journal | vauthors = Côté JF, Motoyama AB, Bush JA | title = A novel and evolutionarily conserved PtdIns(3,4,5)P3-binding domain is necessary for DOCK180 signaling| journal = Nat. Cell Biol. | volume = 7 | issue = 8 | pages = 797–807 |date=August 2005 | pmid = 16025104 | doi = 10.1038/ncb1280| url = | pmc = 1352170 |display-authors=etal}}</ref> and which may be involved in their interaction with [[cell membrane|cellular membranes]]. Other structural features of Dock180 include an [[N-terminal]] [[SH3 domain]] involved in binding to ELMO proteins (see below)<ref name="Brugnera_2002">{{cite journal | vauthors = Brugnera E, Haney L, Grimsley C | title = Unconventional Rac-GEF activity is mediated through the Dock180-ELMO complex| journal = Nat. Cell Biol. | volume = 4 | issue = 8 | pages = 574–82 |date=August 2002 | pmid = 12134158 | doi = 10.1038/ncb824| url = |display-authors=etal}}</ref> 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 (gene)|Crk]]).<ref name="Balagopalan_2006">{{cite journal | vauthors = Balagopalan L, Chen MH, Geisbrecht ER | title = 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| journal = Mol. Cell. Biol. | volume = 26 | issue = 24 | pages = 9442–55 |date=December 2006 | pmid = 17030600 | doi = 10.1128/MCB.00016-06| url = | pmc = 1698515 |display-authors=etal}}</ref>
DOCK180 and related proteins differ from other GEFs in that they do not possess the canonical structure of tandem [[DH domain|DH]]-[[PH domain|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.<ref name="Cote_2002"/> DOCK180-related proteins also possess a [[DHR1 domain]] which has been shown, ''[[in vitro]]'', to bind [[phospholipids]]<ref name="Cote_2005">{{cite journal | vauthors = Côté JF, Motoyama AB, Bush JA | title = A novel and evolutionarily conserved PtdIns(3,4,5)P3-binding domain is necessary for DOCK180 signaling| journal = Nat. Cell Biol. | volume = 7 | issue = 8 | pages = 797–807 |date=August 2005 | pmid = 16025104 | doi = 10.1038/ncb1280| pmc = 1352170 |display-authors=etal}}</ref> and which may be involved in their interaction with [[cell membrane|cellular membranes]]. Other structural features of Dock180 include an [[N-terminal]] [[SH3 domain]] involved in binding to ELMO proteins (see below)<ref name="Brugnera_2002">{{cite journal | vauthors = Brugnera E, Haney L, Grimsley C | title = Unconventional Rac-GEF activity is mediated through the Dock180-ELMO complex| journal = Nat. Cell Biol. | volume = 4 | issue = 8 | pages = 574–82 |date=August 2002 | pmid = 12134158 | doi = 10.1038/ncb824| s2cid = 36363774|display-authors=etal}}</ref> 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 (gene)|Crk]]).<ref name="Balagopalan_2006">{{cite journal | vauthors = Balagopalan L, Chen MH, Geisbrecht ER | title = 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| journal = Mol. Cell. Biol. | volume = 26 | issue = 24 | pages = 9442–55 |date=December 2006 | pmid = 17030600 | doi = 10.1128/MCB.00016-06| pmc = 1698515 |display-authors=etal}}</ref>


==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 book | vauthors = Lu M, Ravichandran KS | chapter = Dock180–ELMO Cooperation in Rac Activation| title = Regulators and Effectors of Small GTPases: Rho Family| volume = 406 | pages = 388–402 | year = 2006 | pmid = 16472672 | doi = 10.1016/S0076-6879(06)06028-9| series = Methods in Enzymology| isbn = 978-0-12-182811-0}}</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| s2cid = 125990|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| s2cid = 14267018|display-authors=etal| doi-access = free | bibcode = 2005CBio...15..371L}}</ref> ELMO1 has also been reported to inhibit [[Ubiquitin|ubiquitinylation]] 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| s2cid = 15035869|display-authors=etal| doi-access = }}</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| bibcode = 2003Natur.424..461K| s2cid = 4411133}}</ref> In [[tumour]] cells DOCK180 is regulated by a complex containing Crk and [[BCAR1|p130Cas]] which is in turn regulated by cooperative signalling by [[Integrin beta 3|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| pmc = 2518715 }}</ref>


==Signalling Downstream of Dock180==
==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'',<ref name="Gumienny_2001">{{cite journal | vauthors = Gumienny TL, Brugnera E, Tosello-Trampont AC| title = CED-12/ELMO, a novel member of the CrkII/Dock180/Rac pathway, is required for phagocytosis and cell migration| journal = Cell | volume = 107 | issue = 1 | pages = 27–41 |date=October 2001 | pmid = 11595183 | doi = 10.1016/S0092-8674(01)00520-7| url = |display-authors=etal}}</ref> [[neurite]] outgrowth in [[PC12 cells]]<ref name="Katoh_2000]">{{cite journal | vauthors = Katoh H, Yasui H, Yamaguchi Y| title = Small GTPase RhoG Is a Key Regulator for Neurite Outgrowth in PC12 Cells| journal = Mol. Cell. Biol. | volume = 20 | issue = 19 | pages = 7378–87 |date=October 2000 | pmid = 10982854 | doi = 10.1128/MCB.20.19.7378-7387.2000| url = | pmc = 86291 |display-authors=etal}}</ref> and [[myoblast]] fusion in the [[Zebrafish]] embryo.<ref name="Moore_2007]">{{cite journal | vauthors = Moore CA, Parkin CA, Bidet Y| title = A role for the Myoblast city homologues Dock1 and Dock5 and the adaptor proteins Crk and Crk-like in zebrafish myoblast fusion| journal = Development | volume = 134 | issue = 17 | pages = 3145–53 |date=September 2007 | pmid = 17670792 | doi = 10.1242/dev.001214| url = |display-authors=etal}}</ref> More recently the DHR1 domain of Dock180 was shown to bind [[SNX5]] (a [[sorting nexin]]) and this interaction promoted retrograde transport of the [[insulin-like growth factor 2 receptor|cation-independent mannose 6-phosphate receptor]] to the [[Golgi apparatus|Trans-Golgi Network]] in a Rac-independent manner.<ref name="Hara_2008]">{{cite journal | vauthors = Hara S, Kiyokawa E, Iemura SI| title = The DHR1 Domain of DOCK180 Binds to SNX5 and Regulates Cation-independent Mannose 6-phosphate Receptor Transport| journal = Mol. Biol. Cell | volume = 19 | issue = 9| pages = 3823–35|date=July 2008 | pmid = 18596235 | doi = 10.1091/mbc.E08-03-0314| url = | pmc = 2526700 |display-authors=etal}}</ref> Increased [[gene expression|expression]] of Dock180 and Elmo has been reported to contribute to [[glioma]] invasion.<ref name="Jarzynka_2007]">{{cite journal | vauthors = Jarzynka MJ, Hu B, Hui KM| title = ELMO1 and Dock180, a Bipartite Rac1 Guanine Nucleotide Exchange Factor, Promote Human Glioma Cell Invasion| journal = Cancer Res. | volume = 67 | issue = 15 | pages = 7203–11 |date=August 2007 | pmid = 17671188 | doi = 10.1158/0008-5472.CAN-07-0473| url = | pmc = 2867339 |display-authors=etal}}</ref>
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'',<ref name="Gumienny_2001">{{cite journal | vauthors = Gumienny TL, Brugnera E, Tosello-Trampont AC | title = CED-12/ELMO, a novel member of the CrkII/Dock180/Rac pathway, is required for phagocytosis and cell migration | journal = Cell | volume = 107 | issue = 1 | pages = 27–41 | date = October 2001 | pmid = 11595183 | doi = 10.1016/S0092-8674(01)00520-7 | s2cid = 15232864 | url = https://www.zora.uzh.ch/id/eprint/952/1/Gumienny2001V.pdf | display-authors = etal | access-date = 2020-09-13 | archive-date = 2021-09-22 | archive-url = https://web.archive.org/web/20210922225900/https://www.zora.uzh.ch/id/eprint/952/1/Gumienny2001V.pdf | url-status = dead }}</ref> [[neurite]] outgrowth in [[PC12 cells]]<ref name="Katoh_2000]">{{cite journal | vauthors = Katoh H, Yasui H, Yamaguchi Y| title = Small GTPase RhoG Is a Key Regulator for Neurite Outgrowth in PC12 Cells| journal = Mol. Cell. Biol. | volume = 20 | issue = 19 | pages = 7378–87 |date=October 2000 | pmid = 10982854 | doi = 10.1128/MCB.20.19.7378-7387.2000| pmc = 86291 |display-authors=etal}}</ref> and [[myoblast]] fusion in the [[zebrafish]] embryo.<ref name="Moore_2007]">{{cite journal | vauthors = Moore CA, Parkin CA, Bidet Y| title = A role for the Myoblast city homologues Dock1 and Dock5 and the adaptor proteins Crk and Crk-like in zebrafish myoblast fusion| journal = Development | volume = 134 | issue = 17 | pages = 3145–53 |date=September 2007 | pmid = 17670792 | doi = 10.1242/dev.001214|display-authors=etal| doi-access = free }}</ref> More recently the DHR1 domain of DOCK180 was shown to bind [[SNX5]] (a [[sorting nexin]]) and this interaction promoted retrograde transport of the [[insulin-like growth factor 2 receptor|cation-independent mannose 6-phosphate receptor]] to the [[Golgi apparatus|trans-Golgi network]] in a Rac-independent manner.<ref name="Hara_2008]">{{cite journal | vauthors = Hara S, Kiyokawa E, Iemura SI| title = The DHR1 Domain of DOCK180 Binds to SNX5 and Regulates Cation-independent Mannose 6-phosphate Receptor Transport| journal = Mol. Biol. Cell | volume = 19 | issue = 9| pages = 3823–35|date=July 2008 | pmid = 18596235 | doi = 10.1091/mbc.E08-03-0314| pmc = 2526700 |display-authors=etal}}</ref> Increased [[gene expression|expression]] of DOCK180 and Elmo has been reported to contribute to [[glioma]] invasion.<ref name="Jarzynka_2007]">{{cite journal | vauthors = Jarzynka MJ, Hu B, Hui KM| title = ELMO1 and Dock180, a Bipartite Rac1 Guanine Nucleotide Exchange Factor, Promote Human Glioma Cell Invasion| journal = Cancer Res. | volume = 67 | issue = 15 | pages = 7203–11 |date=August 2007 | pmid = 17671188 | doi = 10.1158/0008-5472.CAN-07-0473| pmc = 2867339 |display-authors=etal}}</ref>


== Interactions ==
== Interactions ==


Dock180 has been shown to [[Protein-protein interaction|interact]] with:
DOCK180 has been shown to [[Protein-protein interaction|interact]] with:
* [[BCAR1]],<ref name = pmid12615911>{{cite journal | date = Mar 2003 | vauthors = 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 | title = Differential regulation of cell motility and invasion by FAK | journal = J. Cell Biol. | volume = 160 | issue = 5 | pages = 753–67 | pmid = 12615911 | pmc = 2173366 | doi = 10.1083/jcb.200212114}}</ref>
* [[BCAR1]],<ref name = pmid12615911>{{cite journal | date = Mar 2003 | vauthors = 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 | title = Differential regulation of cell motility and invasion by FAK | journal = J. Cell Biol. | volume = 160 | issue = 5 | pages = 753–67 | pmid = 12615911 | pmc = 2173366 | doi = 10.1083/jcb.200212114}}</ref>
* [[CRK (gene)|CRK]]<ref name = pmid12615911/><ref name = pmid8657152/><ref name = pmid10559471>{{cite journal | date = Nov 1999 | vauthors = Nishihara H, Kobayashi S, Hashimoto Y, Ohba F, Mochizuki N, Kurata T, Nagashima K, Matsuda M | title = Non-adherent cell-specific expression of DOCK2, a member of the human CDM-family proteins | journal = Biochim. Biophys. Acta | volume = 1452 | issue = 2 | pages = 179–87 | pmid = 10559471 | doi = 10.1016/s0167-4889(99)00133-0}}</ref><ref name = pmid11369773>{{cite journal | date = Jul 2001 | vauthors = Gu J, Sumida Y, Sanzen N, Sekiguchi K | title = Laminin-10/11 and fibronectin differentially regulate integrin-dependent Rho and Rac activation via p130(Cas)-CrkII-DOCK180 pathway | journal = J. Biol. Chem. | volume = 276 | issue = 29 | pages = 27090–7 | pmid = 11369773 | doi = 10.1074/jbc.M102284200}}</ref><ref name = pmid8662907>{{cite journal | date = Jun 1996 | vauthors = Matsuda M, Ota S, Tanimura R, Nakamura H, Matuoka K, Takenawa T, Nagashima K, Kurata T | title = Interaction between the amino-terminal SH3 domain of CRK and its natural target proteins | journal = J. Biol. Chem. | volume = 271 | issue = 24 | pages = 14468–72 | pmid = 8662907 | doi = 10.1074/jbc.271.24.14468}}</ref>
* [[CRK (gene)|CRK]]<ref name = pmid12615911/><ref name = pmid8657152/><ref name = pmid10559471>{{cite journal | date = Nov 1999 | vauthors = Nishihara H, Kobayashi S, Hashimoto Y, Ohba F, Mochizuki N, Kurata T, Nagashima K, Matsuda M | title = Non-adherent cell-specific expression of DOCK2, a member of the human CDM-family proteins | journal = Biochim. Biophys. Acta | volume = 1452 | issue = 2 | pages = 179–87 | pmid = 10559471 | doi = 10.1016/s0167-4889(99)00133-0| doi-access = free }}</ref><ref name = pmid11369773>{{cite journal | date = Jul 2001 | vauthors = Gu J, Sumida Y, Sanzen N, Sekiguchi K | title = Laminin-10/11 and fibronectin differentially regulate integrin-dependent Rho and Rac activation via p130(Cas)-CrkII-DOCK180 pathway | journal = J. Biol. Chem. | volume = 276 | issue = 29 | pages = 27090–7 | pmid = 11369773 | doi = 10.1074/jbc.M102284200| doi-access = free }}</ref><ref name = pmid8662907>{{cite journal | date = Jun 1996 | vauthors = Matsuda M, Ota S, Tanimura R, Nakamura H, Matuoka K, Takenawa T, Nagashima K, Kurata T | title = Interaction between the amino-terminal SH3 domain of CRK and its natural target proteins | journal = J. Biol. Chem. | volume = 271 | issue = 24 | pages = 14468–72 | pmid = 8662907 | doi = 10.1074/jbc.271.24.14468| doi-access = free }}</ref>
* [[ELMO1]],<ref name = pmid11595183>{{cite journal | date = Oct 2001 | vauthors = 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 | title = CED-12/ELMO, a novel member of the CrkII/Dock180/Rac pathway, is required for phagocytosis and cell migration | journal = Cell | volume = 107 | issue = 1 | pages = 27–41 | pmid = 11595183 | doi = 10.1016/s0092-8674(01)00520-7}}</ref><ref name = pmid12134158>{{cite journal | date = Aug 2002 | vauthors = Brugnera E, Haney L, Grimsley C, Lu M, Walk SF, Tosello-Trampont AC, Macara IG, Madhani H, Fink GR, Ravichandran KS | title = Unconventional Rac-GEF activity is mediated through the Dock180-ELMO complex | journal = Nat. Cell Biol. | volume = 4 | issue = 8 | pages = 574–82 | pmid = 12134158 | doi = 10.1038/ncb824}}</ref> and
* [[ELMO1]],<ref name = pmid11595183>{{cite journal | date = Oct 2001 | vauthors = 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 | title = CED-12/ELMO, a novel member of the CrkII/Dock180/Rac pathway, is required for phagocytosis and cell migration | journal = Cell | volume = 107 | issue = 1 | pages = 27–41 | pmid = 11595183 | doi = 10.1016/s0092-8674(01)00520-7 | s2cid = 15232864 | url = https://www.zora.uzh.ch/id/eprint/952/1/Gumienny2001V.pdf | access-date = 2020-09-13 | archive-date = 2021-09-22 | archive-url = https://web.archive.org/web/20210922225900/https://www.zora.uzh.ch/id/eprint/952/1/Gumienny2001V.pdf | url-status = dead }}</ref><ref name = pmid12134158>{{cite journal | date = Aug 2002 | vauthors = Brugnera E, Haney L, Grimsley C, Lu M, Walk SF, Tosello-Trampont AC, Macara IG, Madhani H, Fink GR, Ravichandran KS | title = Unconventional Rac-GEF activity is mediated through the Dock180-ELMO complex | journal = Nat. Cell Biol. | volume = 4 | issue = 8 | pages = 574–82 | pmid = 12134158 | doi = 10.1038/ncb824| s2cid = 36363774 }}</ref> and
* [[Grb2]].<ref name = pmid12615911/><ref name = pmid8657152>{{cite journal | date = Apr 1996 | vauthors = Hasegawa H, Kiyokawa E, Tanaka S, Nagashima K, Gotoh N, Shibuya M, Kurata T, Matsuda M | title = DOCK180, a major CRK-binding protein, alters cell morphology upon translocation to the cell membrane | journal = Mol. Cell. Biol. | volume = 16 | issue = 4 | pages = 1770–6 | pmid = 8657152 | pmc = 231163 | doi = }}</ref>
* [[Grb2]].<ref name = pmid12615911/><ref name = pmid8657152>{{cite journal | date = Apr 1996 | vauthors = Hasegawa H, Kiyokawa E, Tanaka S, Nagashima K, Gotoh N, Shibuya M, Kurata T, Matsuda M | title = DOCK180, a major CRK-binding protein, alters cell morphology upon translocation to the cell membrane | journal = Mol. Cell. Biol. | volume = 16 | issue = 4 | pages = 1770–6 | pmid = 8657152 | pmc = 231163 | doi = 10.1128/MCB.16.4.1770}}</ref>


==References==
==References==
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==Further reading==
==Further reading==
{{refbegin | 2}}
{{refbegin | 2}}
{{PBB_Further_reading
| citations =
*{{cite journal | vauthors=Takai S, Hasegawa H, Kiyokawa E |title=Chromosomal mapping of the gene encoding DOCK180, a major Crk-binding protein, to 10q26.13-q26.3 by fluorescence in situ hybridization |journal=Genomics |volume=35 |issue= 2 |pages= 403–4 |year= 1996 |pmid= 8661160 |doi=10.1006/geno.1996.0378 |display-authors=etal}}
*{{cite journal | vauthors=Takai S, Hasegawa H, Kiyokawa E |title=Chromosomal mapping of the gene encoding DOCK180, a major Crk-binding protein, to 10q26.13-q26.3 by fluorescence in situ hybridization |journal=Genomics |volume=35 |issue= 2 |pages= 403–4 |year= 1996 |pmid= 8661160 |doi=10.1006/geno.1996.0378 |display-authors=etal}}
*{{cite journal | vauthors=Côté JF, Vuori K |title=GEF what? Dock180 and related proteins help Rac to polarize cells in new ways |journal=Trends Cell Biol. |volume=17 |issue= 8 |pages= 383–93 |year= 2007 |pmid= 17765544 | pmc=2887429 |doi=10.1016/j.tcb.2007.05.001 }}
*{{cite journal | vauthors=Côté JF, Vuori K |title=GEF what? Dock180 and related proteins help Rac to polarize cells in new ways |journal=Trends Cell Biol. |volume=17 |issue= 8 |pages= 383–93 |year= 2007 |pmid= 17765544 | pmc=2887429 |doi=10.1016/j.tcb.2007.05.001 }}
*{{cite journal | vauthors=Komander D, Patel M, Laurin M |title=An α-Helical Extension of the ELMO1 Pleckstrin Homology Domain Mediates Direct Interaction to DOCK180 and Is Critical in Rac Signaling |journal=Mol. Biol. Cell |volume=19 |issue= 11|pages=4837–51|year= 2008 |pmid= 18768751 |doi=10.1091/mbc.E08-04-0345 | pmc=2575150 |display-authors=etal}}
*{{cite journal | vauthors=Komander D, Patel M, Laurin M |title=An α-Helical Extension of the ELMO1 Pleckstrin Homology Domain Mediates Direct Interaction to DOCK180 and Is Critical in Rac Signaling |journal=Mol. Biol. Cell |volume=19 |issue= 11|pages=4837–51|year= 2008 |pmid= 18768751 |doi=10.1091/mbc.E08-04-0345 | pmc=2575150 |display-authors=etal}}
*{{cite journal | author=Henson PM |title=Engulfment: ingestion and migration with Rac, Rho and TRIO |journal=Curr. Biol. |volume=15 |issue= 1 |pages= R29–30 |year= 2005 |pmid= 15649349 |doi=10.1016/j.cub.2004.12.017 }}
*{{cite journal | author=Henson PM |title=Engulfment: ingestion and migration with Rac, Rho and TRIO |journal=Curr. Biol. |volume=15 |issue= 1 |pages= R29–30 |year= 2005 |pmid= 15649349 |doi=10.1016/j.cub.2004.12.017 |doi-access=free |bibcode=2005CBio...15..R29H }}
*{{cite journal | vauthors=deBakker CD, Haney LB, Kinchen JM |title=Phagocytosis of apoptotic cells is regulated by a UNC-73/TRIO-MIG-2/RhoG signaling module and armadillo repeats of CED-12/ELMO |journal=Curr. Biol. |volume=14 |issue= 24 |pages= 2208–16 |year= 2004 |pmid= 15620647 |doi=10.1016/j.cub.2004.12.029 |display-authors=etal}}
*{{cite journal | vauthors=deBakker CD, Haney LB, Kinchen JM |title=Phagocytosis of apoptotic cells is regulated by a UNC-73/TRIO-MIG-2/RhoG signaling module and armadillo repeats of CED-12/ELMO |journal=Curr. Biol. |volume=14 |issue= 24 |pages= 2208–16 |year= 2004 |pmid= 15620647 |doi=10.1016/j.cub.2004.12.029 |s2cid=1269946 |display-authors=etal|doi-access=free |bibcode=2004CBio...14.2208D }}
*{{cite journal | vauthors=Yin J, Haney L, Walk S |title=Nuclear localization of the DOCK180/ELMO complex |journal=Arch. Biochem. Biophys. |volume=429 |issue= 1 |pages= 23–29 |year= 2004 |pmid= 15288806 |doi=10.1016/j.abb.2004.05.014 |display-authors=etal}}
*{{cite journal |vauthors=Yin J, Haney L, Walk S |title=Nuclear localization of the DOCK180/ELMO complex |journal=Arch. Biochem. Biophys. |volume=429 |issue=1 |pages=23–29 |year=2004 |pmid=15288806 |doi=10.1016/j.abb.2004.05.014 |display-authors=etal |url=https://zenodo.org/record/1258672 }}
*{{cite journal | vauthors=Matsuda M, Ota S, Tanimura R |title=Interaction between the amino-terminal SH3 domain of CRK and its natural target proteins |journal=J. Biol. Chem. |volume=271 |issue= 24 |pages= 14468–72 |year= 1996 |pmid= 8662907 |doi=10.1074/jbc.271.24.14468 |display-authors=etal}}
*{{cite journal | vauthors=Matsuda M, Ota S, Tanimura R |title=Interaction between the amino-terminal SH3 domain of CRK and its natural target proteins |journal=J. Biol. Chem. |volume=271 |issue= 24 |pages= 14468–72 |year= 1996 |pmid= 8662907 |doi=10.1074/jbc.271.24.14468 |display-authors=etal|doi-access=free }}
*{{cite journal | author=Savill J |title=Apoptosis. Phagocytic docking without shocking |journal=Nature |volume=392 |issue= 6675 |pages= 442–3 |year= 1998 |pmid= 9548247 |doi=10.1038/33025 }}
*{{cite journal | author=Savill J |title=Apoptosis. Phagocytic docking without shocking |journal=Nature |volume=392 |issue= 6675 |pages= 442–3 |year= 1998 |pmid= 9548247 |doi=10.1038/33025 |bibcode=1998Natur.392..442S |s2cid=205002296 |doi-access=free }}
*{{cite journal | vauthors=Wu YC, Horvitz HR |title=C. elegans phagocytosis and cell-migration protein CED-5 is similar to human DOCK180 |journal=Nature |volume=392 |issue= 6675 |pages= 501–4 |year= 1998 |pmid= 9548255 |doi=10.1038/33163 }}
*{{cite journal | vauthors=Wu YC, Horvitz HR |title=C. elegans phagocytosis and cell-migration protein CED-5 is similar to human DOCK180 |journal=Nature |volume=392 |issue= 6675 |pages= 501–4 |year= 1998 |pmid= 9548255 |doi=10.1038/33163 |bibcode=1998Natur.392..501W |s2cid=205002377 }}
*{{cite journal | vauthors=Albert ML, Kim JI, Birge RB |title=alphavbeta5 integrin recruits the CrkII-Dock180-rac1 complex for phagocytosis of apoptotic cells |journal=Nat. Cell Biol. |volume=2 |issue= 12 |pages= 899–905 |year= 2001 |pmid= 11146654 |doi=10.1038/35046549 }}
*{{cite journal | vauthors=Albert ML, Kim JI, Birge RB |title=alphavbeta5 integrin recruits the CrkII-Dock180-rac1 complex for phagocytosis of apoptotic cells |journal=Nat. Cell Biol. |volume=2 |issue= 12 |pages= 899–905 |year= 2001 |pmid= 11146654 |doi=10.1038/35046549 |s2cid=7535200 }}
*{{cite journal | vauthors=Kobayashi S, Shirai T, Kiyokawa E |title=Membrane recruitment of DOCK180 by binding to PtdIns(3,4,5)P3 |journal=Biochem. J. |volume=354 |issue= Pt 1 |pages= 73–8 |year= 2001 |pmid= 11171081 |doi=10.1042/0264-6021:3540073 | pmc=1221630 |display-authors=etal}}
*{{cite journal | vauthors=Kobayashi S, Shirai T, Kiyokawa E |title=Membrane recruitment of DOCK180 by binding to PtdIns(3,4,5)P3 |journal=Biochem. J. |volume=354 |issue= Pt 1 |pages= 73–8 |year= 2001 |pmid= 11171081 |doi=10.1042/0264-6021:3540073 | pmc=1221630 |display-authors=etal}}
*{{cite journal | vauthors=Tu Y, Kucik DF, Wu C |title=Identification and kinetic analysis of the interaction between Nck-2 and DOCK180 |journal=FEBS Lett. |volume=491 |issue= 3 |pages= 193–9 |year= 2001 |pmid= 11240126 |doi=10.1016/S0014-5793(01)02195-0 }}
*{{cite journal | vauthors=Tu Y, Kucik DF, Wu C |title=Identification and kinetic analysis of the interaction between Nck-2 and DOCK180 |journal=FEBS Lett. |volume=491 |issue= 3 |pages= 193–9 |year= 2001 |pmid= 11240126 |doi=10.1016/S0014-5793(01)02195-0 |s2cid=31372015 |doi-access=free |bibcode=2001FEBSL.491..193T }}
*{{cite journal | vauthors=Gu J, Sumida Y, Sanzen N, Sekiguchi K |title=Laminin-10/11 and fibronectin differentially regulate integrin-dependent Rho and Rac activation via p130(Cas)-CrkII-DOCK180 pathway |journal=J. Biol. Chem. |volume=276 |issue= 29 |pages= 27090–7 |year= 2001 |pmid= 11369773 |doi=10.1074/jbc.M102284200 }}
*{{cite journal | vauthors=Gu J, Sumida Y, Sanzen N, Sekiguchi K |title=Laminin-10/11 and fibronectin differentially regulate integrin-dependent Rho and Rac activation via p130(Cas)-CrkII-DOCK180 pathway |journal=J. Biol. Chem. |volume=276 |issue= 29 |pages= 27090–7 |year= 2001 |pmid= 11369773 |doi=10.1074/jbc.M102284200 |doi-access=free }}
*{{cite journal | vauthors=Zhou Z, Caron E, Hartwieg E |title=The C. elegans PH domain protein CED-12 regulates cytoskeletal reorganization via a Rho/Rac GTPase signaling pathway |journal=Dev. Cell |volume=1 |issue= 4 |pages= 477–89 |year= 2001 |pmid= 11703939 |doi=10.1016/S1534-5807(01)00058-2 |display-authors=etal}}
*{{cite journal | vauthors=Zhou Z, Caron E, Hartwieg E |title=The C. elegans PH domain protein CED-12 regulates cytoskeletal reorganization via a Rho/Rac GTPase signaling pathway |journal=Dev. Cell |volume=1 |issue= 4 |pages= 477–89 |year= 2001 |pmid= 11703939 |doi=10.1016/S1534-5807(01)00058-2 |display-authors=etal|doi-access=free }}
*{{cite journal | vauthors=Grimsley CM, Kinchen JM, Tosello-Trampont AC |title=Dock180 and ELMO1 proteins cooperate to promote evolutionarily conserved Rac-dependent cell migration |journal=J. Biol. Chem. |volume=279 |issue= 7 |pages= 6087–97 |year= 2004 |pmid= 14638695 |doi=10.1074/jbc.M307087200 |display-authors=etal}}
*{{cite journal |vauthors=Grimsley CM, Kinchen JM, Tosello-Trampont AC |title=Dock180 and ELMO1 proteins cooperate to promote evolutionarily conserved Rac-dependent cell migration |journal=J. Biol. Chem. |volume=279 |issue=7 |pages=6087–97 |year=2004 |pmid=14638695 |doi=10.1074/jbc.M307087200 |s2cid=2324987 |display-authors=etal |doi-access=free }}
*{{cite journal | vauthors=Wang X, Wu YC, Fadok VA |title=Cell corpse engulfment mediated by C. elegans phosphatidylserine receptor through CED-5 and CED-12 |journal=Science |volume=302 |issue= 5650 |pages= 1563–6 |year= 2003 |pmid= 14645848 |doi=10.1126/science.1087641 |display-authors=etal}}
*{{cite journal |vauthors=Wang X, Wu YC, Fadok VA |title=Cell corpse engulfment mediated by C. elegans phosphatidylserine receptor through CED-5 and CED-12 |journal=Science |volume=302 |issue=5650 |pages=1563–6 |year=2003 |pmid=14645848 |doi=10.1126/science.1087641 |bibcode=2003Sci...302.1563W |s2cid=25672278 |url=http://ntur.lib.ntu.edu.tw/bitstream/246246/161415/1/06.pdf |display-authors=etal }}
}}
{{refend}}
{{refend}}


==External links==
==External links==
* {{MeshName|DOCK1+protein,+human}}
* {{MeshName|DOCK1+protein,+human}}
*[http://cmkb.cellmigration.org/report.cgi?report=orth_overview&gene_id=1793 DOCK180] Info with links in the [http://www.cellmigration.org/index.shtml Cell Migration Gateway]
*[https://web.archive.org/web/20110706174151/http://cmkb.cellmigration.org/report.cgi?report=orth_overview&gene_id=1793 DOCK180] Info with links in the [http://www.cellmigration.org/index.shtml Cell Migration Gateway] {{Webarchive|url=https://web.archive.org/web/20141211173306/http://www.cellmigration.org/index.shtml |date=2014-12-11 }}
* {{PDBe-KB2|Q14185|Dedicator of cytokinesis protein 1}}


{{GTP-binding protein regulators}}
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Latest revision as of 11:38, 15 November 2024

DOCK1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesDOCK1, DOCK180, ced5, Dock180, dedicator of cytokinesis 1
External IDsOMIM: 601403; MGI: 2429765; HomoloGene: 55575; GeneCards: DOCK1; OMA:DOCK1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

1793

330662

Ensembl

ENSG00000150760

ENSMUSG00000058325

UniProt

Q14185

Q8BUR4

RefSeq (mRNA)

NM_001290223
NM_001380

NM_001033420

RefSeq (protein)

NP_001028592

Location (UCSC)Chr 10: 126.91 – 127.45 MbChr 7: 134.27 – 134.78 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[5] It is the mammalian ortholog of the C. elegans protein CED-5 and belongs to the DOCK family of guanine nucleotide exchange factors (GEFs).[6]

Discovery

[edit]

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.[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

[edit]

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-terminal SH3 domain involved in binding to ELMO proteins (see below)[11] 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).[12]

Regulation of DOCK180 Activity

[edit]

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 ubiquitinylation 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-containing integrin complexes and the membrane-bound protein uPAR.[18]

Signalling Downstream of DOCK180

[edit]

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,[19] neurite outgrowth in PC12 cells[20] and myoblast fusion in the zebrafish embryo.[21] 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.[22] Increased expression of DOCK180 and Elmo has been reported to contribute to glioma invasion.[23]

Interactions

[edit]

DOCK180 has been shown to interact with:

References

[edit]
  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000150760 – Ensembl, May 2017
  2. ^ a b c 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".
  6. ^ 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. S2CID 3075895.
  7. ^ 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. PMC 231163. PMID 8657152.
  8. ^ 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.
  9. ^ a b 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. S2CID 14669715.
  10. ^ 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.
  11. ^ a b 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. S2CID 36363774.
  12. ^ 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.
  13. ^ 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. ISBN 978-0-12-182811-0. PMID 16472672.
  14. ^ 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.
  15. ^ 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.
  16. ^ 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. S2CID 15035869.
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Further reading

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