DOCK7
Encyclopedia
Dock7 also known as Zir2, is a large (~240 kDa) protein
involved in intracellular
signalling networks. It is a member of the DOCK-C subfamily of the DOCK
family of guanine nucleotide exchange factor
s (GEFs) which function as activators of small G proteins. Dock7 activates isoforms of the small G protein Rac
.
s and in the HEK 293 cell line.
(GDP) and their activation requires the dissociation of GDP and binding of guanosine triphosphate
(GTP). GEFs activate G proteins by promoting this nucleotide exchange.
Dock7 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 G protein activation by stabilising it in its nucleotide free state. They also contain a DHR1 domain
which, in many DOCK family members, interacts with phospholipids. Dock7 shares the highest level of sequence similarity with Dock6
and Dock8
, the other members of the DOCK-C subfamily. However, the specificity of the Dock7 DHR2 domain appears to resemble that of DOCK-A/B subfamily proteins in that it binds Rac but not Cdc42
. Many DOCK family proteins contain important structural features at their N- and C-termini, however, these regions in Dock7 are poorly characterised thus far and no such features have been identified.
s mediated via domains at their N- and C-termini, however, the mechanisms by which Dock7 is regulated are largely unknown. There is evidence that the production of PtdIns(3,4,5)P3
by members of the Phosphoinositide 3-kinase
(PI3K) family is important for efficient recruitment of Dock7 since the PI3K inhibitor LY294002
was shown to block Dock7-dependent functions in neurons. This observation is consistent with the role of the DHR1 domain in other DOCK family proteins. In neurons of the hippocampus
Dock7 undergoes striking changes in subcellular localisation during the progressive stages of neuronal development, resulting in an abundance of this protein in a single neurite
which goes on to form the axon
of the polarised neuron.
In Schwann cell
s (which generate an insulating layer, known as the myelin sheath
, around axons of the peripheral nervous system
) Dock7 appears to be activated downstream of the neuregulin
receptor ErbB2, which receives signals from the axon that induce Schwann cell proliferation, migration and myelination. ErbB2 has been shown to tyrosine
phosphorylate
Dock7 and thus promote Schwann cell migration.
and Rac3
. This work suggests that Dock7 is a key mediator of the process that specifies which of the many neurites will become the axon. Indeed, overexpression of Dock7 induced the formation of multiple axons and RNA interference
knock-down of Dock7 prevented axon formation. In Schwann cells Dock7 was shown to regulate the activation of Cdc42 as well as Rac1 however no direct interaction between Dock7 and Cdc42 has been demonstrated. Dock7 has also been reported to interact with the TSC1
-TSC2
(also known as hamartin-tuberin) complex, the normal function of which is disrupted in sufferers of Tuberous sclerosis
. It was subsequently suggested that Dock7 may function as a GEF for Rheb
, a small G protein that functions downstream of the TSC1-TSC2 complex. Although DOCK family proteins are generally considered as GEFs specific for Rho family G proteins Dock4
has been shown to bind and activate Rap1
, which is not a member of the Rho family. This apparent promiscuity among DOCK proteins and their targets, coupled with the fact that Rheb is highly expressed in the brain means that Dock7 GEF activity towards Rheb, although not yet demonstrated, would not be surprising.
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-C 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 proteins. Dock7 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
Dock7 was identified as one of a number of proteins which share high sequence similarity with the previously described protein Dock180, the archetypal member of the DOCK family. Dock7 expression has been reported in neuronNeuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s and in the HEK 293 cell line.
Structure and function
Dock7 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.
Dock7 and other DOCK family proteins differ from other GEFs in that they do not possess the canonical structure of tandem DH
RhoGEF domain
RhoGEF domain is a structural domain of guanine nucleotide exchange factors for Rho/Rac/Cdc42-like GTPases. It is also called "Dbl-homologous" domain.-Human proteins containing this domain :...
-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 G protein 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, in many DOCK family members, interacts with phospholipids. Dock7 shares the highest level of sequence similarity with Dock6
Dock6
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.-Discovery:Dock6 was identified as one of a family of...
and Dock8
DOCK8
Dock8 , also known as Zir3, 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.-Discovery:Dock8 was identified during a yeast two hybrid...
, the other members of the DOCK-C subfamily. However, the specificity of the Dock7 DHR2 domain appears to resemble that of DOCK-A/B subfamily proteins in that it binds Rac but not Cdc42
CDC42
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 :...
. Many DOCK family proteins contain important structural features at their N- and C-termini, however, these regions in Dock7 are poorly characterised thus far and no such features have been identified.
Regulation of Dock7 Activity
Many members of the DOCK family are regulated by protein-protein interactionProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
s mediated via domains at their N- and C-termini, however, the mechanisms by which Dock7 is regulated are largely unknown. There is evidence that the production of 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:...
by members of the Phosphoinositide 3-kinase
Phosphoinositide 3-kinase
Phosphatidylinositol 3-kinases are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. In response to lipopolysaccharide, PI3K phosphorylates p65, inducing...
(PI3K) family is important for efficient recruitment of Dock7 since the PI3K inhibitor LY294002
LY294002
LY294002 is a morpholine derivative of quercetin. It is a potent inhibitor of phosphoinositide 3-kinases . Two of these are the proto-oncogene serine/threonine-protein kinase and the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform...
was shown to block Dock7-dependent functions in neurons. This observation is consistent with the role of the DHR1 domain in other DOCK family proteins. In neurons of the hippocampus
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...
Dock7 undergoes striking changes in subcellular localisation during the progressive stages of neuronal development, resulting in an abundance of this protein in a single neurite
Neurite
A neurite refers to any projection from the cell body of a neuron. This projection can be either an axon or a dendrite. The term is frequently used when speaking of immature or developing neurons, especially of cells in culture, because it can be difficult to tell axons from dendrites before...
which goes on to form the axon
Axon
An axon is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma....
of the polarised neuron.
In Schwann cell
Schwann cell
Schwann cells or neurolemmocytes are the principal glia of the peripheral nervous system . Glial cells function to support neurons and in the PNS, also include satellite cells, olfactory ensheathing cells, enteric glia and glia that reside at sensory nerve endings, such as the Pacinian corpuscle...
s (which generate an insulating layer, known as the myelin sheath
Myelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
, around axons of the peripheral nervous system
Peripheral nervous system
The peripheral nervous system consists of the nerves and ganglia outside of the brain and spinal cord. The main function of the PNS is to connect the central nervous system to the limbs and organs. Unlike the CNS, the PNS is not protected by the bone of spine and skull, or by the blood–brain...
) Dock7 appears to be activated downstream of the neuregulin
Neuregulin
The Neuregulins are a family of four structurally-related proteins that are part of the EGF family of proteins. These proteins have been shown to have diverse functions in the development of the nervous system and play multiple essential roles in vertebrate embryogenesis including: cardiac...
receptor ErbB2, which receives signals from the axon that induce Schwann cell proliferation, migration and myelination. ErbB2 has been shown to tyrosine
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
phosphorylate
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
Dock7 and thus promote Schwann cell migration.
Signalling downstream of Dock7
DOCK proteins are known activators of small G proteins of the Rho family. A study of Dock7 in HEK 293 cells and hippocampal neurons has shown that it can bind and promote nucleotide exchange on the Rac subfamily isoforms 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 Rac3
Rac3
Rac3 is a small monomeric GTP-binding protein G protein and is an important component of 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 RAC3....
. This work suggests that Dock7 is a key mediator of the process that specifies which of the many neurites will become the axon. Indeed, overexpression of Dock7 induced the formation of multiple axons and RNA interference
RNA interference
RNA interference is a process within living cells that moderates the activity of their genes. Historically, it was known by other names, including co-suppression, post transcriptional gene silencing , and quelling. Only after these apparently unrelated processes were fully understood did it become...
knock-down of Dock7 prevented axon formation. In Schwann cells Dock7 was shown to regulate the activation of Cdc42 as well as Rac1 however no direct interaction between Dock7 and Cdc42 has been demonstrated. Dock7 has also been reported to interact with the TSC1
TSC1
Tuberous sclerosis protein 1, also known as TSC1 or hamartin, is a human protein and gene.- Function :This peripheral membrane protein was implicated as a tumor suppressor...
-TSC2
TSC2
Tuberous sclerosis protein 2, also known as TSC2 and Tuberin, is a human protein and gene.-Interactions:TSC2 has been shown to interact with FOXO1, GSK3B, Peptidylglycine alpha-amidating monooxygenase, RAP1A, MAPK1, AKT1, AXIN1, TSC1, PTK2, Protein kinase, AMP-activated, alpha 1, YWHAZ, RPS6KA1,...
(also known as hamartin-tuberin) complex, the normal function of which is disrupted in sufferers of Tuberous sclerosis
Tuberous sclerosis
Tuberous sclerosis or tuberous sclerosis complex is a rare multi-system genetic disease that causes non-malignant tumors to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin. A combination of symptoms may include seizures, developmental delay, behavioral...
. It was subsequently suggested that Dock7 may function as a GEF for Rheb
RHEB
GTP-binding protein Rheb also known as Ras homolog enriched in brain is a protein that in humans is encoded by the RHEB gene.- Function :Rheb is a recently discovered member of the Ras superfamily that may be involved in neural plasticity...
, a small G protein that functions downstream of the TSC1-TSC2 complex. Although DOCK family proteins are generally considered as GEFs specific for Rho family G proteins Dock4
DOCK4
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 which function as activators of small G proteins...
has been shown to bind and activate 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...
, which is not a member of the Rho family. This apparent promiscuity among DOCK proteins and their targets, coupled with the fact that Rheb is highly expressed in the brain means that Dock7 GEF activity towards Rheb, although not yet demonstrated, would not be surprising.