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Dedicator of cytokinesis protein 1
Protein found in humans From Wikipedia, the free encyclopedia
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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]
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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]
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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 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
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]
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Interactions
DOCK180 has been shown to interact with:
References
Further reading
External links
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