Dock2

Dock2 ( D edicator o f c yto k inesis 2), also known as DOCK2, is a large (~180 kDa) is_associated_with::protein involved in is_associated_with::intracellular signalling networks. It is a member of the DOCK-A subfamily of the DOCK family of is_associated_with::guanine nucleotide exchange factors (GEFs) which function as activators of small is_associated_with::G proteins. Dock2 specifically activates isoforms of the small G protein Rac.

Discovery
Dock2 was first characterised as one of a number of proteins which shared high is_associated_with::sequence similarity with the previously described protein is_associated_with::Dock180, the archetypal member of the DOCK family. Whereas Dock180 expression is near ubiquitous in mammals, Dock2 appears to be expressed specifically in is_associated_with::leukocytes and is considered to be the principal DOCK family member in these cells.

Structure and Function
Dock2 is part of a large class of proteins (GEFs) which contibrute to cellular signalling events by activating small G proteins. In their resting state G proteins are bound to is_associated_with::Guanosine diphosphate (GDP) and their activation requires the dissociation of GDP and binding of is_associated_with::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 is_associated_with::DHR2 domain which mediates Rac activation by stabilising it in its nucleotide-free state. They also contain a is_associated_with::DHR1 domain which binds is_associated_with::phospholipids and is required for the interaction between Dock2 and the is_associated_with::plasma membrane. As with other members of the DOCK-A and DOCK-B subfamilies, Dock2 contains an is_associated_with::N-terminal is_associated_with::SH3 domain which is involved in binding to ELMO proteins (see below). Dock180 contains a is_associated_with::C-terminal is_associated_with::proline rich region which mediates binding to Crk, however, Dock2 lacks this feature despite the fact that it is able to bind the Crk-like protein CrkL.

Regulation of Dock2 activity
Efficient Dock180 GEF activity in a cellular context is known to require the formation of a complex between Dock180 and its cognate is_associated_with::adaptor proteins, which assist its translocation to the plasma mambrane and binding to Rac. Similarly, Dock2 has been shown to form a complex with the well described DOCK-binding protein is_associated_with::ELMO1 and this interaction is required for Dock2-mediated Rac activation in is_associated_with::lymphocyte cell lines. 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). ELMO proteins also contain a is_associated_with::PH domain which appears to induce is_associated_with::conformational changes in DOCK and thus allow binding to Rac.

Signalling downstream of Dock2
Like other DOCK-A and DOCK-B subfamily proteins Dock2 GEF activity is specific for Rac. Leukocytes express both is_associated_with::Rac1 and is_associated_with::Rac2 and Dock2 has been shown to bind and promote nucleotide exchange on both of these is_associated_with::isoforms. Rac isoforms regulate a multitude of processes in leukocytes and studies so far have shown that Dock2-dependent Rac activation regulates the is_associated_with::neutrophil is_associated_with::NADPH oxidase and is also important for is_associated_with::chemotaxis in neutrophils, lymphocytes and plasmacytoid dendritic cells. Dock2-dependent NADPH oxidase activation was reported in response to the soluble is_associated_with::agonist fMLP, which acts via is_associated_with::G protein-coupled receptors in neutrophils. Dock2-dependent chemotaxis has been reported in response to the is_associated_with::chemokines CXCL12/SDF-1 in is_associated_with::T lymphocytes, CXCL13/BLC in is_associated_with::B lymphocytes and CCL19/ELC in is_associated_with::thymocytes (immature lymphocytes) emigrating from the is_associated_with::thymus as well as CCL21/SLC in is_associated_with::ex vivo plasmacytoid dendritic cells. In neutrophil chemotaxis Dock2 signals downstream of the C5a and CXCL8/IL-8 receptors. Additional receptors which signal through Dock2 include the T cell receptor/TCR and is_associated_with::EDG1, a sphingosine-1-phosphate (S1P) receptor. Interestingly, the is_associated_with::HIV-1 protein Nef is able to constitutively activate Dock2 in T lymphocytes which disrups chemotaxis and is_associated_with::immunological synapse formation thereby inhibiting the antiviral is_associated_with::immune response.

Interactions
Dock2 has been shown to interact with is_associated_with::CRKL.