DOCK8
Encyclopedia
Dock8 also known as Zir3, is a large (~190 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.
(YTH) screen for proteins that interact with the Rho family small G protein Cdc42
. Subsequent northern blot
analysis revealed high levels of Dock8 expression in the placenta
, lung
, kidney
and pancreas
as well as lower levels in the heart
, brain
and skeletal muscle
.
which, in other proteins, contains GEF activity and a DHR1 domain
known, in other proteins, to interact with phospholipids. In the YTH system Dock8 was reported to interact with both Rac1
and Cdc42. However, no stable interaction between Dock8 and these small G proteins was observed in a GST-pulldown assay
. This may be due to the fact many DOCK-G protein interactions require the presence of adaptor protein
s to stabilise the complex and thus facilitate nucleotide exchange.
of Dock8 have been reported in a human lung cancer
cell line and Dock8 was also identified as a putative candidate gene associated with progression of glioma
s. Interestingly, Dock8 has been reported to be disrupted in two unrelated patients with mental retardation
.
Autosomal recessive DOCK8 deficiency is associated with a variant of combined immunodeficiency. This variant of Hyperimmunoglobulin E syndrome (HIES) was first described in 2004 and was now found to have a genetic mutation in the DOCK8 gene.
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.
Discovery
Dock8 was identified during a yeast two hybridTwo-hybrid screening
Two-hybrid screening is a molecular biology technique used to discover protein–protein interactions and protein–DNA interactions by testing for physical interactions between two proteins or a single protein and a DNA molecule, respectively.The premise behind the test is the activation of...
(YTH) screen for proteins that interact with the Rho family small G protein 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 :...
. 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 Dock8 expression in the 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...
, lung
Lung
The lung is the essential respiration organ in many air-breathing animals, including most tetrapods, a few fish and a few snails. In mammals and the more complex life forms, the two lungs are located near the backbone on either side of the heart...
, kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
and pancreas
Pancreas
The pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as a digestive organ, secreting pancreatic juice containing digestive enzymes that assist...
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...
, brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
and 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...
.
Function
Dock8 shares the same core domain arrangement as all other DOCK proteins, with a DHR2 domainDHR2 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, in other proteins, contains GEF activity 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...
known, in other proteins, to interact with phospholipids. In the YTH system Dock8 was reported to interact with both Rac1
RAC1
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 Cdc42. However, no stable interaction between Dock8 and these small G proteins was observed in a GST-pulldown assay
Glutathione S-transferase
Enzymes of the glutathione S-transferase family are composed of many cytosolic, mitochondrial, and microsomal proteins. GSTs are present in eukaryotes and in prokaryotes, where they catalyze a variety of reactions and accept endogenous and xenobiotic substrates.GSTs can constitute up to 10% of...
. This may be due to the fact many DOCK-G protein interactions require the presence of 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 to stabilise the complex and thus facilitate nucleotide exchange.
Dock8 in disease
Despite the fact that little is known about the cellular role of Dock8 its importance has been highlighted in several studies which have identified distruption of the DOCK8 gene in disease. Deletion and reduced 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...
of Dock8 have been reported in a human lung cancer
Lung cancer
Lung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body. Most cancers that start in lung, known as primary...
cell line and Dock8 was also identified as a putative candidate gene associated with progression of glioma
Glioma
A glioma is a type of tumor that starts in the brain or spine. It is called a glioma because it arises from glial cells. The most common site of gliomas is the brain.-By type of cell:...
s. Interestingly, Dock8 has been reported to be disrupted in two unrelated patients with mental retardation
Mental retardation
Mental retardation is a generalized disorder appearing before adulthood, characterized by significantly impaired cognitive functioning and deficits in two or more adaptive behaviors...
.
Autosomal recessive DOCK8 deficiency is associated with a variant of combined immunodeficiency. This variant of Hyperimmunoglobulin E syndrome (HIES) was first described in 2004 and was now found to have a genetic mutation in the DOCK8 gene.