DOCK2
Encyclopedia
Dock2 also known as DOCK2, is a large (~180 kDa) 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
.
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.
(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. They also contain a DHR1 domain
which binds phospholipids and is required for the interaction between Dock2 and the plasma membrane. 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). Dock180 contains a C-terminal 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
.
between Dock180 and its cognate adaptor protein
s, 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 ELMO1
and this interaction is required for Dock2-mediated Rac activation in 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 PH domain which appears to induce conformational change
s in DOCK and thus allow binding to Rac.
and Rac2
and Dock2 has been shown to bind and promote nucleotide exchange on both of these isoforms. 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
and is also important for chemotaxis
in neutrophils, lymphocytes and plasmacytoid dendritic cells
. Dock2-dependent NADPH oxidase activation was reported in response to the soluble agonist
fMLP
, which acts via G protein-coupled receptor
s in neutrophils. 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 thymocyte
s (immature lymphocytes) emigrating from the thymus
as well as CCL21/SLC
in 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 EDG1
, a sphingosine-1-phosphate (S1P)
receptor. Interestingly, the HIV-1 protein Nef is able to constitutively activate Dock2 in T lymphocytes which disrups chemotaxis and immunological synapse
formation thereby inhibiting the antiviral immune response.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
involved in intracellular
Intracellular
Not to be confused with intercellular, meaning "between cells".In cell biology, molecular biology and related fields, the word intracellular means "inside the cell".It is used in contrast to extracellular...
signalling networks. It is a member of the DOCK-A subfamily of the DOCK
DOCK (protein)
DOCK is a family of related proteins involved in intracellular signalling networks. Studies to date suggest that this family act as guanine nucleotide exchange factors for small G proteins of the Rho family, such as Rac and Cdc42...
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
Rac (GTPase)
Rac is a subfamily of the Rho family of GTPases, small signaling G proteins .The subgroup include:*Rac1*Rac2*Rac3*RhoG...
.
Discovery
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 expressionGene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
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.
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 Guanosine diphosphateGuanosine diphosphate
Guanosine diphosphate, abbreviated GDP, is a nucleoside diphosphate. It is an ester of pyrophosphoric acid with the nucleoside guanosine. GDP consists of the pyrophosphate group, the pentose sugar ribose, and the nucleobase guanine....
(GDP) and their activation requires the dissociation of GDP and binding of guanosine triphosphate
Guanosine triphosphate
Guanosine-5'-triphosphate is a purine nucleoside triphosphate. It can act as a substrate for the synthesis of RNA during the transcription process...
(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
DHR2 domain
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 domain for small G proteins of the Rho family...
which mediates Rac activation by stabilising it in its nucleotide-free state. They also contain a DHR1 domain
DHR1 domain
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...
which binds phospholipids and is required for the interaction between Dock2 and the plasma membrane. As with other members of the DOCK-A and DOCK-B subfamilies, Dock2 contains an N-terminal SH3 domain
SH3 domain
The SRC Homology 3 Domain is a small protein domain of about 60 amino acids residues first identified as a conserved sequence in the viral adaptor protein v-Crk and the non-catalytic parts of enzymes such as phospholipase and several cytoplasmic tyrosine kinases such as Abl and Src...
which is involved in binding to ELMO
ELMO (protein)
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.This family...
proteins (see below). Dock180 contains a C-terminal proline
Proline
Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...
rich region which mediates binding to Crk
CRK (gene)
Adapter molecule crk also known as proto-oncogene c-Crk or p38 is a protein that in humans is encoded by the CRK gene.- Function :...
, however, Dock2 lacks this feature despite the fact that it is able to bind the Crk-like protein CrkL
CRKL
Crk-like protein is a protein that in humans is encoded by the CRKL gene.CrkL together with Crk participates in the Reelin signaling cascade downstream of DAB1.-Interactions:...
.
Regulation of Dock2 activity
Efficient Dock180 GEF activity in a cellular context is known to require the formation of a complexProtein complex
A multiprotein complex is a group of two or more associated polypeptide chains. If the different polypeptide chains contain different protein domain, the resulting multiprotein complex can have multiple catalytic functions...
between Dock180 and its cognate adaptor protein
Adaptor protein
Signal transducing adaptor proteins are proteins which are accessory to main proteins in a signal transduction pathway. These proteins tend to lack any intrinsic enzymatic activity themselves but instead mediate specific protein–protein interactions that drive the formation of protein complexes...
s, 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 ELMO1
ELMO1
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.- Structure :...
and this interaction is required for Dock2-mediated Rac activation in lymphocyte
Lymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...
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 PH domain which appears to induce conformational change
Conformational change
A macromolecule is usually flexible and dynamic. It can change its shape in response to changes in its environment or other factors; each possible shape is called a conformation, and a transition between them is called a conformational change...
s 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 Rac1RAC1
Ras-related C3 botulinum toxin substrate 1 also known as Rac1 is a protein that in humans is encoded by the RAC1 gene. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined.- Function :Rac1 is...
and Rac2
Rac2
Rac2 is a small signaling G protein , and is a member of the Rac subfamily of the family Rho family of GTPases...
and Dock2 has been shown to bind and promote nucleotide exchange on both of these isoforms. 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
NADPH oxidase
The NADPH oxidase is a membrane-bound enzyme complex. It can be found in the plasma membrane as well as in the membrane of phagosome.-Subunits:It is made up of six subunits...
and is also important for chemotaxis
Chemotaxis
Chemotaxis is the phenomenon in which somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemicals in their environment. This is important for bacteria to find food by swimming towards the highest concentration of food molecules,...
in neutrophils, lymphocytes and plasmacytoid dendritic cells
Dendritic cell
Dendritic cells are immune cells forming part of the mammalian immune system. Their main function is to process antigen material and present it on the surface to other cells of the immune system. That is, dendritic cells function as antigen-presenting cells...
. Dock2-dependent NADPH oxidase activation was reported in response to the soluble agonist
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
fMLP
N-Formylmethionine leucyl-phenylalanine
N-Formylmethionyl-leucyl-phenylalanine is a formylated tripeptide originally isolated from bacterial filtrates that is positively chemotactic to polymorphonuclear leucocytes, and causes them to release lysosomal enzymes and become "metabolically activated" N-Formylmethionyl-leucyl-phenylalanine is...
, which acts via G protein-coupled receptor
G protein-coupled receptor
G protein-coupled receptors , also known as seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors , comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal...
s in neutrophils. Dock2-dependent chemotaxis has been reported in response to the chemokines CXCL12/SDF-1 in T lymphocytes, CXCL13/BLC
CXCL13
C-X-C motif chemokine 13 also known as B lymphocyte chemoattractant is a protein that in humans is encoded by the CXCL13 gene.- Function :CXCL13 is a small cytokine belonging to the CXC chemokine family...
in B lymphocytes and CCL19/ELC
CCL19
C-C motif chemokine 19 is a protein that in humans is encoded by the CCL19 gene.Chemokine ligand 19 is a small cytokine belonging to the CC chemokine family that is also known as EBI1 ligand chemokine and macrophage inflammatory protein-3-beta...
in thymocyte
Thymocyte
Thymocytes are hematopoietic progenitor cells present in the thymus. Thymopoiesis is the process in the thymus by which thymocytes differentiate into mature T lymphocytes. The primary function of thymocytes is the generation of T lymphocytes . The thymus provides an inductive environment, which...
s (immature lymphocytes) emigrating from the thymus
Thymus
The thymus is a specialized organ of the immune system. The thymus produces and "educates" T-lymphocytes , which are critical cells of the adaptive immune system....
as well as CCL21/SLC
CCL21
Chemokine ligand 21 is a small cytokine belonging to the CC chemokine family. This chemokine is also known as 6Ckine , exodus-2, and secondary lymphoid-tissue chemokine . The gene for CCL21 is located on human chromosome 9...
in ex vivo
Ex vivo
Ex vivo means that which takes place outside an organism. In science, ex vivo refers to experimentation or measurements done in or on tissue in an artificial environment outside the organism with the minimum alteration of natural conditions...
plasmacytoid dendritic cells. In neutrophil chemotaxis Dock2 signals downstream of the C5a
C5a
C5a is a protein fragment released from complement component C5. In humans, the polypeptide contains 74 amino acids. NMR spectroscopy proved that the molecule is composed of four helices and loops connecting the helices. On the N terminus a short 1.5 turn helix is also present. The longest helix...
and CXCL8/IL-8
Interleukin 8
Interleukin-8 is a chemokine produced by macrophages and other cell types such as epithelial cells. It is also synthesized by endothelial cells, which store IL-8 in their storage vesicles, the Weibel-Palade bodies...
receptors. Additional receptors which signal through Dock2 include the T cell receptor/TCR
T cell receptor
The T cell receptor or TCR is a molecule found on the surface of T lymphocytes that is responsible for recognizing antigens bound to major histocompatibility complex molecules...
and EDG1
EDG1
S1PR1 also known as S1P1 or EDG1 is a protein that in humans is encoded by the S1PR1 gene...
, a sphingosine-1-phosphate (S1P)
Sphingosine-1-phosphate
Sphingosine-1-phosphate is a signaling sphingolipid. It is also referred to as a bioactive lipid mediator. Sphingolipids at large form a class of lipids characterized by a particular aliphatic aminoalcohol, which is sphingosine.-Production:...
receptor. Interestingly, the HIV-1 protein Nef is able to constitutively activate Dock2 in T lymphocytes which disrups chemotaxis and immunological synapse
Immunological synapse
In immunology, an immunological synapse is the interface between an antigen-presenting cell and a lymphocyte. It was first discovered by Abraham Kupfer at the National Jewish Medical and Research Center in Denver and the term was coined by Michael Dustin at NYU who studied it in further detail...
formation thereby inhibiting the antiviral immune response.