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]
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]
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]
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]
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]
DOCK180 has been shown to interact with:
Guanine nucleotide exchange factors (GEFs) are proteins or protein domains that activate monomeric GTPases by stimulating the release of guanosine diphosphate (GDP) to allow binding of guanosine triphosphate (GTP). A variety of unrelated structural domains have been shown to exhibit guanine nucleotide exchange activity. Some GEFs can activate multiple GTPases while others are specific to a single GTPase.
Adapter molecule crk also known as proto-oncogene c-Crk is a protein that in humans is encoded by the CRK gene.
The Rho family of GTPases is a family of small signaling G proteins, and is a subfamily of the Ras superfamily. The members of the Rho GTPase family have been shown to regulate many aspects of intracellular actin dynamics, and are found in all eukaryotic kingdoms, including yeasts and some plants. Three members of the family have been studied in detail: Cdc42, Rac1, and RhoA. All G proteins are "molecular switches", and Rho proteins play a role in organelle development, cytoskeletal dynamics, cell movement, and other common cellular functions.
Rho guanine nucleotide exchange factor 6 is a protein that, in humans, is encoded by the ARHGEF6 gene.
Guanine nucleotide exchange factor VAV2 is a protein that in humans is encoded by the VAV2 gene.
Engulfment and cell motility protein 1 is a protein that in humans is encoded by the ELMO1 gene. ELMO1 is located on chromosome number seven in humans and is located on chromosome number thirteen in mice.
RhoG is a small monomeric GTP-binding protein, and is an important component of many intracellular signalling pathways. It is a member of the Rac subfamily of the Rho family of small G proteins and is encoded by the gene RHOG.
Dedicator of cytokinesis protein 2 (Dock2) is a protein encoded in the human by the DOCK2 gene. Dock2 is a large protein involved in intracellular signalling networks. It is a member of the DOCK-A subfamily of the DOCK family of guanine nucleotide exchange factors (GEFs) which function as activators of small G-proteins. Dock2 specifically activates isoforms of the small G protein Rac.
Engulfment and cell motility protein 2 is a protein that in humans is encoded by the ELMO2 gene.
Dedicator of cytokinesis protein (Dock7) is a large protein encoded in the human by the DOCK7 gene, involved in intracellular signalling networks. It is a member of the DOCK-C subfamily of the DOCK family of guanine nucleotide exchange factors (GEFs) which function as activators of small G-proteins. Dock7 activates isoforms of the small G protein Rac.
Dedicator of cytokinesis protein 4 (Dock4), is a large protein encoded in the human by the DOCK4 gene, involved in intracellular signalling networks. It is a member of the DOCK-B subfamily of the DOCK family of guanine nucleotide exchange factors (GEFs) which function as activators of small G-proteins. Dock4 activates the small G proteins Rac and Rap1.
Dedicator of cytokinesis protein 3 (Dock3), also known as MOCA and PBP, is a large protein encoded in the human by the DOCK3 gene, involved in intracellular signalling networks. It is a member of the DOCK-B subfamily of the DOCK family of guanine nucleotide exchange factors (GEFs) which function as activators of small G-proteins. Dock3 specifically activates the small G protein Rac.
Dedicator of cytokinesis protein 9 (Dock9), also known as Zizimin1, is a large protein encoded in the human by the DOCK9 gene, involved in intracellular signalling networks. It is a member of the DOCK-D subfamily of the DOCK family of guanine nucleotide exchange factors that function as activators of small G-proteins. Dock9 activates the small G protein Cdc42.
ELMO is a family of related proteins (~82 kDa) involved in intracellular signalling networks. These proteins have no intrinsic catalytic activity and instead function as adaptors which can regulate the activity of other proteins through their ability to mediate protein-protein interactions.
CED-12 is a cytoplasmic, PH-domain containing adaptor protein found in Caenorhabditis elegans and Drosophila melanogaster. CED-12 is a homolog to the ELMO protein found in mammals. This protein is involved in Rac-GTPase activation, apoptotic cell phagocytosis, cell migration, and cytoskeletal rearrangements.
DHR1, also known as CZH1 or Docker1, is a protein domain of approximately 200–250 amino acids that is present in the DOCK family of signalling proteins. This domain binds phospholipids and so may assist in recruitment to cellular membranes. There is evidence that this domain may also mediate protein–protein interactions.
DHR2, also known as CZH2 or Docker2, is a protein domain of approximately 450-550 amino acids that is present in the DOCK family of proteins. This domain functions as a guanine nucleotide exchange factor (GEF) domain for small G proteins of the Rho family. DHR2 domains bear no significant similarity to the well described DH domain present in other RhoGEFs such as Vav, P-Rex and TRIO. Indeed, the most divergent mammalian DHR2 domains share only 16-17% sequence similarity.
Dedicator of cytokinesis protein 5 (Dock5) is a large protein encoded in the human by the DOCK5 gene, involved in intracellular signalling networks. It is a member of the DOCK-A subfamily of the DOCK family of guanine nucleotide exchange factors (GEFs) which function as activators of small G-proteins. Dock5 is predicted to activate the small G protein Rac.
Dedicator of cytokinesis protein 6 (Dock6), also known as Zir1 is a large protein encoded in the human by the DOCK6 gene, involved in intracellular signalling networks. It is a member of the DOCK-C subfamily of the DOCK family of guanine nucleotide exchange factors which function as activators of small G-proteins.
Dedicator of cytokinesis protein 11 (Dock11), also known as Zizimin2, is a large protein encoded in the human by the DOCK11 gene, involved in intracellular signalling networks. It is a member of the DOCK-D subfamily of the DOCK family of guanine nucleotide exchange factors (GEFs) which function as activators of small G-proteins. Dock11 activates the small G protein Cdc42.
