DOCK4
Encyclopedia
Dock4, also known as DOCK4, is a large (~190 kDa) protein
involved in intracellular
signalling networks. It is a member of the DOCK-B subfamily of the DOCK
family of guanine nucleotide exchange factor
s (GEFs) which function as activators of small G protein
s. Dock4 activates the small G proteins Rac
and Rap1
.
which was disrupted during tumour progression in a murine cancer model-derived osteosarcoma
cell line. Subsequent Northern blot
analysis revealed high levels of Dock4 expression
in skeletal muscle
, prostate
and ovary
as well as lower levels in the heart
, placenta
and colon
. A separate study has reported expression of a Dock4 splice variant
(Dock4-Ex49
) in the brain, inner ear
and eye.
(GDP) and their activation requires the dissociation of GDP and binding of guanosine triphosphate
(GTP). GEFs activate G proteins by promoting this nucleotide exchange.
The domain arrangement of Dock4 is largely equivalent to that of Dock180 (the archetypal member of the DOCK
family) and other DOCK-A/B family members (35% sequence identity
with Dock180, 39% with Dock2
and 54% with Dock3
). Dock4, however, contains a unique set of motifs
at its proline
-rich C-terminus which include a Src
-binding site that is shared with CED-5, the C. elegans
ortholog of mammalian DOCK proteins. Dock4 also contains a DHR2 domain
(also known as Docker2 or CZH2) which is conserved among DOCK family proteins and mediates GEF-dependent functions, and a DHR1 domain
(CZH1/Docker1) which has been shown to bind PtdIns(3,4,5)P3
, an important step in recruitment to the plasma membrane.
in their resting state. The adaptor protein
ELMO
has been shown to bind DOCK proteins and induce a conformational change which relieves the inhibition and allows G proteins access to the DHR2 domain. Binding to ELMO requires the atypical PH domain of ELMO and also involves an interaction between the N-terminal SH3 domain
of DOCK and a proline-rich motif at the ELMO C-terminus. ELMO also binds the activated form of the small G protein RhoG
and this has been shown to promote DOCK-dependent signalling by helping recruit the ELMO-DOCK complex
to areas of high substrate
availability (usually the plasma membrane). The C-terminus of DOCK proteins interacts with another adaptor protein, Crk
. Dock4 undergoes RhoG/ELMO-dependent recruitment to the plasma membrane and promotes migration
in fibroblasts. In rat hippocampal
neurones Dock4 forms a trimeric complex with ELMO2
and CrkII which is required for the normal development of dendrite
s. More recently, a role has been described for Dock4 as part of the Wnt signalling pathway which regulates cell proliferation and migration. In this system Dock4 was reported to undergo phosphorylation
by Glycogen synthase kinase 3 (GSK-3) which stimulated an increase in Dock4 GEF activity.
. Interestingly, Dock4 has also been shown to activate Rap1, a feature not reported in any of the other DOCK family proteins to date. Dock4 dependent Rac activation regulates reorganisation of the cytoskeleton
and leads to the formation of membrane protrusions (e.g. lamellipodia
) which are a crucial step in neuronal development and cell migration. The effect of Dock4 on the Wnt pathway appears to be mediated through Rac activation as well as through GEF-independent associations with components of the "β-catenin
degradation complex".
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-B 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 factor
Guanine nucleotide exchange factor
Guanine nucleotide exchange factors activate monomeric GTPases by stimulating the release of guanosine diphosphate to allow binding of guanosine triphosphate . A variety of unrelated structural domains have been shown to exhibit guanine nucleotide exchange activity...
s (GEFs) which function as activators of small G protein
G protein
G proteins are a family of proteins involved in transmitting chemical signals outside the cell, and causing changes inside the cell. They communicate signals from many hormones, neurotransmitters, and other signaling factors. G protein-coupled receptors are transmembrane receptors...
s. Dock4 activates the small G proteins Rac
Rac (GTPase)
Rac is a subfamily of the Rho family of GTPases, small signaling G proteins .The subgroup include:*Rac1*Rac2*Rac3*RhoG...
and Rap1
Rap GTP-binding protein
Rap GTP-binding protein also known as Ras-related proteins or simply RAP is a type of small GTPase, similar in structure to Ras.These proteins share approximately 50% amino acid identity with the classical RAS proteins and have numerous structural features in common...
.
Discovery
Dock4 was discovered as a gene productGene product
A gene product is the biochemical material, either RNA or protein, resulting from expression of a gene. A measurement of the amount of gene product is sometimes used to infer how active a gene is. Abnormal amounts of gene product can be correlated with disease-causing alleles, such as the...
which was disrupted during tumour progression in a murine cancer model-derived osteosarcoma
Osteosarcoma
Osteosarcoma is an aggressive cancerous neoplasm arising from primitive transformed cells of mesenchymal origin that exhibit osteoblastic differentiation and produce malignant osteoid...
cell line. Subsequent Northern blot
Northern blot
The northern blot is a technique used in molecular biology research to study gene expression by detection of RNA in a sample. With northern blotting it is possible to observe cellular control over structure and function by determining the particular gene expression levels during differentiation,...
analysis revealed high levels of Dock4 expression
Gene 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...
in skeletal muscle
Skeletal muscle
Skeletal muscle is a form of striated muscle tissue existing under control of the somatic nervous system- i.e. it is voluntarily controlled. It is one of three major muscle types, the others being cardiac and smooth muscle...
, prostate
Prostate
The prostate is a compound tubuloalveolar exocrine gland of the male reproductive system in most mammals....
and ovary
Ovary
The ovary is an ovum-producing reproductive organ, often found in pairs as part of the vertebrate female reproductive system. Ovaries in anatomically female individuals are analogous to testes in anatomically male individuals, in that they are both gonads and endocrine glands.-Human anatomy:Ovaries...
as well as lower levels in the heart
Heart
The heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...
, placenta
Placenta
The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...
and colon
Colon (anatomy)
The colon is the last part of the digestive system in most vertebrates; it extracts water and salt from solid wastes before they are eliminated from the body, and is the site in which flora-aided fermentation of unabsorbed material occurs. Unlike the small intestine, the colon does not play a...
. A separate study has reported expression of a Dock4 splice variant
Alternative splicing
Alternative splicing is a process by which the exons of the RNA produced by transcription of a gene are reconnected in multiple ways during RNA splicing...
(Dock4-Ex49
Dock4-Ex49
Dock4-Ex49 is a splice variant of the signalling protein Dock4 . It has been found in the brain, inner ear and eye. It is able to bind and activate the small G protein Rac and may regulate the organisation of the actin cytoskeleton in the Stereocilia of the inner ear....
) in the brain, inner ear
Inner ear
The inner ear is the innermost part of the vertebrate ear. In mammals, it consists of the bony labyrinth, a hollow cavity in the temporal bone of the skull with a system of passages comprising two main functional parts:...
and eye.
Structure and Function
Dock4 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.
The domain arrangement of Dock4 is largely equivalent to that of Dock180 (the archetypal member 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) and other DOCK-A/B family members (35% sequence identity
Sequence alignment
In bioinformatics, a sequence alignment is a way of arranging the sequences of DNA, RNA, or protein to identify regions of similarity that may be a consequence of functional, structural, or evolutionary relationships between the sequences. Aligned sequences of nucleotide or amino acid residues are...
with Dock180, 39% with Dock2
DOCK2
Dock2 , also known as 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 which function as activators of small G proteins...
and 54% with Dock3
DOCK3
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 which function as activators of small G proteins...
). Dock4, however, contains a unique set of motifs
Structural motif
In a chain-like biological molecule, such as a protein or nucleic acid, a structural motif is a supersecondary structure, which appears also in a variety of other molecules...
at its 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 C-terminus which include a Src
Src (gene)
Proto-oncogene tyrosine-protein kinase Src is an enzyme that in humans is encoded by the SRC gene.Src is a proto-oncogene encoding a tyrosine kinase originally discovered by J. Michael Bishop and Harold E. Varmus, for which they won the 1989 Nobel Prize in Physiology or Medicine. It belongs to a...
-binding site that is shared with CED-5, the C. elegans
Caenorhabditis elegans
Caenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...
ortholog of mammalian DOCK proteins. Dock4 also contains 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...
(also known as Docker2 or CZH2) which is conserved among DOCK family proteins and mediates GEF-dependent functions, and 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...
(CZH1/Docker1) which has been shown to bind PtdIns(3,4,5)P3
Phosphatidylinositol (3,4,5)-trisphosphate
Phosphatidylinositol -triphosphate , abbreviated PIP3, is the product of the class I phosphoinositide 3-kinases phosphorylation on phosphatidylinositol -bisphosphate .-Discovery:...
, an important step in recruitment to the plasma membrane.
Regulation of Dock4 Activity
DOCK family proteins are inefficient at promoting nucleotide exchange on their own since they appear to adopt an autoinhibitory conformationProtein folding
Protein folding is the process by which a protein structure assumes its functional shape or conformation. It is the physical process by which a polypeptide folds into its characteristic and functional three-dimensional structure from random coil....
in their resting state. The 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...
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...
has been shown to bind DOCK proteins and induce a conformational change which relieves the inhibition and allows G proteins access to the DHR2 domain. Binding to ELMO requires the atypical PH domain of ELMO and also involves an interaction between the 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...
of DOCK and a proline-rich motif at the ELMO C-terminus. ELMO also binds the activated form of the small G protein RhoG
RhoG
RhoG is a small monomeric GTP-binding protein , and is an important component of many intracellular signalling pathways...
and this has been shown to promote DOCK-dependent signalling by helping recruit the ELMO-DOCK complex
Protein 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...
to areas of high substrate
Substrate (biochemistry)
In biochemistry, a substrate is a molecule upon which an enzyme acts. Enzymes catalyze chemical reactions involving the substrate. In the case of a single substrate, the substrate binds with the enzyme active site, and an enzyme-substrate complex is formed. The substrate is transformed into one or...
availability (usually the plasma membrane). The C-terminus of DOCK proteins interacts with another adaptor protein, 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 :...
. Dock4 undergoes RhoG/ELMO-dependent recruitment to the plasma membrane and promotes migration
Cell migration
Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryonic development, wound healing and immune responses all require the orchestrated movement of cells in particular directions to specific locations...
in fibroblasts. In rat hippocampal
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
neurones Dock4 forms a trimeric complex with ELMO2
ELMO2
Engulfment and cell motility protein 2 is a protein that in humans is encoded by the ELMO2 gene.-Further reading:...
and CrkII which is required for the normal development of dendrite
Dendrite
Dendrites are the branched projections of a neuron that act to conduct the electrochemical stimulation received from other neural cells to the cell body, or soma, of the neuron from which the dendrites project...
s. More recently, a role has been described for Dock4 as part of the Wnt signalling pathway which regulates cell proliferation and migration. In this system Dock4 was reported to undergo phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
by Glycogen synthase kinase 3 (GSK-3) which stimulated an increase in Dock4 GEF activity.
Signalling Downstream of Dock4
DOCK family proteins contribute to cell signalling by activating G proteins of the Rho family, such as Rac and Cdc42CDC42
Cell division control protein 42 homolog also known as CDC42 is a protein involved in regulation of the cell cycle. In humans, CDC42 is encoded by the CDC42 gene.- Function :...
. Interestingly, Dock4 has also been shown to activate Rap1, a feature not reported in any of the other DOCK family proteins to date. Dock4 dependent Rac activation regulates reorganisation of the cytoskeleton
Cytoskeleton
The cytoskeleton is a cellular "scaffolding" or "skeleton" contained within a cell's cytoplasm and is made out of protein. The cytoskeleton is present in all cells; it was once thought to be unique to eukaryotes, but recent research has identified the prokaryotic cytoskeleton...
and leads to the formation of membrane protrusions (e.g. lamellipodia
Lamellipodia
The lamellipodium is a cytoskeletal protein actin projection on the mobile edge of the cell. It contains a quasi-two-dimensional actin mesh; the whole structure propels the cell across a substrate...
) which are a crucial step in neuronal development and cell migration. The effect of Dock4 on the Wnt pathway appears to be mediated through Rac activation as well as through GEF-independent associations with components of the "β-catenin
Beta-catenin
Beta-catenin is a protein that in humans is encoded by the CTNNB1 gene. In Drosophila, the homologous protein is called armadillo...
degradation complex".