Dock180

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:

• BCAR1,^[20]
• CRK^{[20][21][22][23][24]}
• ELMO1,^[25][26] and
• Grb2.^[20][21]

References

Further reading

External links

• DOCK1 protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)
• DOCK180 Info with links in the Cell Migration Gateway