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Protein found in humans
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
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
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
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 -containing
integrin complexes and the membrane-bound protein
uPAR .
[18]
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 ,
[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
DOCK180 has been shown to
interact with:
References
^
a
b
c
GRCh38: Ensembl release 89: ENSG00000150760 –
Ensembl , May 2017
^
a
b
c
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" .
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^ 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.
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^
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b
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^
a
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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 .
PMC
2887429 .
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 .
PMC
2575150 .
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 .
Savill J (1998).
"Apoptosis. Phagocytic docking without shocking" . Nature . 392 (6675): 442–3.
Bibcode :
1998Natur.392..442S .
doi :
10.1038/33025 .
PMID
9548247 .
S2CID
205002296 .
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 .
PMC
1221630 .
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.
Bibcode :
2001FEBSL.491..193T .
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 .
External links