Dock2 (Dedicator of cytokinesis 2), also known as DOCK2, is a large (~180 kDa) protein involved in intracellular signalling networks. [5] 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.
Dock2 was first characterised as one of a number of proteins which shared high sequence similarity with the previously described protein Dock180, the archetypal member of the DOCK family. Whereas Dock180 expression is near ubiquitous in mammals, Dock2 appears to be expressed specifically in leukocytes and is considered to be the principal DOCK family member in these cells. [6]
Dock2 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.
Dock2 and other DOCK family 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. [7] They also contain a DHR1 domain which binds phospholipids and is required for the interaction between Dock2 and the plasma membrane. [8] As with other members of the DOCK-A and DOCK-B subfamilies, Dock2 contains an N-terminal SH3 domain which is involved in binding to ELMO proteins (see below). [9] Dock180 contains a C-terminal proline rich region which mediates binding to Crk, however, Dock2 lacks this feature [6] despite the fact that it is able to bind the Crk-like protein CrkL. [10]
Efficient Dock180 GEF activity in a cellular context is known to require the formation of a complex between Dock180 and its cognate adaptor proteins, which assist its translocation to the plasma membrane and binding to Rac. [11] [12] Similarly, Dock2 has been shown to form a complex with the well described DOCK-binding protein ELMO1 and this interaction is required for Dock2-mediated Rac activation in lymphocyte cell lines. [9] ELMO proteins contain a C-terminal proline-rich region which binds to the N-terminal SH3 domain of DOCK proteins and mediates their recruitment to sites of high Rac availability (primarily the plasma membrane). [12] ELMO proteins also contain a PH domain which appears to induce conformational changes in DOCK and thus allow binding to Rac. [13]
Like other DOCK-A and DOCK-B subfamily proteins Dock2 GEF activity is specific for Rac. Leukocytes express both Rac1 and Rac2 and Dock2 has been shown to bind and promote nucleotide exchange on both of these isoforms. [6] Rac isoforms regulate a multitude of processes in leukocytes and studies so far have shown that Dock2-dependent Rac activation regulates the neutrophil NADPH oxidase [8] and is also important for chemotaxis in neutrophils, [8] [14] lymphocytes [15] and plasmacytoid dendritic cells. [16] Dock2-dependent NADPH oxidase activation was reported in response to the soluble agonist fMLP, which acts via G protein-coupled receptors in neutrophils. [8] Dock2-dependent chemotaxis has been reported in response to the chemokines CXCL12/SDF-1 in T lymphocytes, CXCL13/BLC in B lymphocytes and CCL19/ELC in thymocytes (immature lymphocytes) emigrating from the thymus [15] as well as CCL21/SLC in ex vivo plasmacytoid dendritic cells. [16] In neutrophil chemotaxis Dock2 signals downstream of the C5a and CXCL8/IL-8 receptors. [8] [14] Additional receptors which signal through Dock2 include the T cell receptor/TCR [17] and EDG1, a sphingosine-1-phosphate (S1P) receptor. [18] The HIV-1 protein Nef is able to constitutively activate Dock2 in T lymphocytes which disrupts chemotaxis and immunological synapse formation thereby inhibiting the antiviral immune response. [19]
Chemokines, or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In addition to playing a major role in the activation of host immune responses, chemokines are important for biological processes, including morphogenesis and wound healing, as well as in the pathogenesis of diseases like cancers.
Interleukin 8 is a chemokine produced by macrophages and other cell types such as epithelial cells, airway smooth muscle cells and endothelial cells. Endothelial cells store IL-8 in their storage vesicles, the Weibel-Palade bodies. In humans, the interleukin-8 protein is encoded by the CXCL8 gene. IL-8 is initially produced as a precursor peptide of 99 amino acids which then undergoes cleavage to create several active IL-8 isoforms. In culture, a 72 amino acid peptide is the major form secreted by macrophages.
Macrophage Inflammatory Proteins (MIP) belong to the family of chemotactic cytokines known as chemokines. In humans, there are two major forms, MIP-1α and MIP-1β that are now officially named CCL3 and CCL4, respectively. But we can sometimes encounter other names, especially in older literature, as LD78α, AT 464.1 and GOS19-1 for human CCL3 and AT 744, Act-2, LAG-1, HC21 and G-26 for human CCL4. Other macrophage inflammatory proteins include MIP-2, MIP-3 and MIP-5.
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.
CXC chemokine receptors are integral membrane proteins that specifically bind and respond to cytokines of the CXC chemokine family. They represent one subfamily of chemokine receptors, a large family of G protein-linked receptors that are known as seven transmembrane (7-TM) proteins, since they span the cell membrane seven times. There are currently six known CXC chemokine receptors in mammals, named CXCR1 through CXCR6.
Dock180, also known as DOCK1, is a large protein involved in intracellular signalling networks. It is the mammalian ortholog of the C. elegans protein CED-5 and belongs to the DOCK family of Guanine nucleotide exchange factors (GEFs).
This gene encodes a member of the G protein-coupled receptor kinase subfamily of the Ser/Thr protein kinase family, and is most highly similar to GRK4 and GRK5. The protein phosphorylates the activated forms of G protein-coupled receptors to regulate their signaling.
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.
Dock7, also known as Zir2, is a large protein 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.
Dock4, also known as DOCK4, is a large protein 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.
Dock3, also known as MOCA and PBP, is a large protein 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.
Dock9, also known as Zizimin1, is a large protein 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 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.
Dock5, also known as DOCK5, 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. Dock5 is predicted to activate the small G protein Rac.
Dock6, also known as Zir1 is a large protein 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.
Dock11, also known as Zizimin2, is a large protein 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.
Chemorepulsion is the directional movement of a cell away from a substance. Of the two directional varieties of chemotaxis, chemoattraction has been studied to a much greater extent. Only recently have the key components of the chemorepulsive pathway been elucidated. The exact mechanism is still being investigated, and its constituents are currently being explored as likely candidates for immunotherapies.
