Dedicator of cytokinesis protein 11 (Dock11), also known as Zizimin2, is a large (~240 kDa)
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
encoded in the human by the ''DOCK11'' gene, involved in
intracellular
This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...
signalling networks.
It is a member of the DOCK-D subfamily of the
DOCK
The word dock () in American English refers to one or a group of human-made structures that are involved in the handling of boats or ships (usually on or near a shore). In British English, the term is not used the same way as in American Engl ...
family of
guanine nucleotide exchange factor
Guanine nucleotide exchange factors (GEFs) are proteins or protein domains that activate monomeric GTPases by stimulating the release of guanosine diphosphate (GDP) to allow binding of guanosine triphosphate (GTP). A variety of unrelated structu ...
s (GEFs) which function as activators of
small G-protein
Small GTPases (), also known as small G-proteins, are a family of hydrolase enzymes that can bind and hydrolyze guanosine triphosphate (GTP). They are a type of G-protein found in the cytosol that are homologous to the alpha subunit of heterotrim ...
s. Dock11 activates the small G protein
Cdc42
Cell division control protein 42 homolog (Cdc42 or CDC42) is a protein that in humans is encoded by the ''CDC42'' gene. Cdc42 is involved in regulation of the cell cycle. It was originally identified in ''S. cerevisiae'' (yeast) as a mediator of ...
.
Discovery
Dock11 was identified as a protein which is highly
expressed in
germinal center
Germinal centers or germinal centres (GCs) are transiently formed structures within B cell zone (follicles) in secondary lymphoid organs – lymph nodes, ileal Peyer's patches, and the spleen – where mature B cells are activated, prolifera ...
B lymphocytes
B cells, also known as B lymphocytes, are a type of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasm ...
.
Subsequent
RT-PCR
Reverse transcription polymerase chain reaction (RT-PCR) is a laboratory technique combining reverse transcription of RNA into DNA (in this context called complementary DNA or cDNA) and amplification of specific DNA targets using polymerase chain ...
analysis revealed expression of this protein in the
spleen
The spleen (, from Ancient Greek '' σπλήν'', splḗn) is an organ (biology), organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter.
The spleen plays important roles in reg ...
,
thymus
The thymus (: thymuses or thymi) is a specialized primary lymphoid organ of the immune system. Within the thymus, T cells mature. T cells are critical to the adaptive immune system, where the body adapts to specific foreign invaders. The thymus ...
,
bone marrow
Bone marrow is a semi-solid biological tissue, tissue found within the Spongy bone, spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It i ...
and in
peripheral blood lymphocytes
Peripheral blood lymphocytes (PBLs) are mature lymphocytes that circulate in the blood, rather than localizing to organs (such as the spleen or lymph nodes). They comprise T cells, NK cells and B cells
B cells, also known as B lymphocytes, are ...
. Dock11 is expressed at lower levels in
NIH-3T3 fibroblasts, C2C12
myoblast
Myogenesis is the formation of skeletal muscular tissue, particularly during embryonic development.
Muscle fibers generally form through the fusion of precursor myoblasts into multinucleated fibers called myotubes. In the early development o ...
s and Neuro-2A
neuroblastoma
Neuroblastoma (NB) is a type of cancer that forms in certain types of nerve tissue. It most frequently starts from one of the adrenal glands but can also develop in the head, neck, chest, abdomen, or Vertebral column, spine. Symptoms may include ...
cells. Dock11
mRNA
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein.
mRNA is ...
has also been detected in the
pars intermedia
The pars intermedia is one of the three parts of the anterior pituitary. It is a section of tissue sometimes called a middle or intermediate lobe, between the pars distalis, and the posterior pituitary. It is a small region that is largely with ...
.
Structure and function
Dock11 exhibits the same
domain
A domain is a geographic area controlled by a single person or organization. Domain may also refer to:
Law and human geography
* Demesne, in English common law and other Medieval European contexts, lands directly managed by their holder rather ...
arrangement as other members of the DOCK-D/Zizimin subfamily and shares the highest level of sequence identity with
Dock9
Dedicator of cytokinesis protein 9 (Dock9), also known as Zizimin1, is a large (~230 kDa) protein encoded in the human by the ''DOCK9'' gene, involved in intracellular signalling networks. It is a member of the DOCK-D subfamily of the DOCK famil ...
.
It contains a
DHR2 domain
DHR2 (DOCK homology region 2), 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 (GEF) domain for sm ...
which mediates GEF activity and a
DHR1 domain
DHR1 (DOCK homology region 1), 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 ...
which may interact with
membrane
A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. Bi ...
phospholipid
Phospholipids are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typ ...
s. It also contains an
N-terminal
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...
PH domain
Pleckstrin homology domain (PH domain) or (PHIP) is a protein domain of approximately 120 amino acids that occurs in a wide range of proteins involved in intracellular signaling or as constituents of the cytoskeleton.
This domain can bind phosph ...
which may be involved in its recruitment to the
plasma membrane
The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...
. Dock11 binds and activates
nucleotide
Nucleotides are Organic compound, organic molecules composed of a nitrogenous base, a pentose sugar and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both o ...
-free Cdc42 via its DHR2 domain
and has also been reported to mediate
positive feedback
Positive feedback (exacerbating feedback, self-reinforcing feedback) is a process that occurs in a feedback loop where the outcome of a process reinforces the inciting process to build momentum. As such, these forces can exacerbate the effects ...
on active,
GTP-bound Cdc42,
although this interaction required a small N-terminal region of Dock11 in addition to the DHR2 domain. Cdc42 in turn regulates signaling pathways that control diverse cellular functions including
morphology
Morphology, from the Greek and meaning "study of shape", may refer to:
Disciplines
*Morphology (archaeology), study of the shapes or forms of artifacts
*Morphology (astronomy), study of the shape of astronomical objects such as nebulae, galaxies, ...
,
migration
Migration, migratory, or migrate may refer to: Human migration
* Human migration, physical movement by humans from one region to another
** International migration, when peoples cross state boundaries and stay in the host state for some minimum le ...
,
endocytosis
Endocytosis is a cellular process in which Chemical substance, substances are brought into the cell. The material to be internalized is surrounded by an area of cell membrane, which then buds off inside the cell to form a Vesicle (biology and chem ...
and
cell cycle
The cell cycle, or cell-division cycle, is the sequential series of events that take place in a cell (biology), cell that causes it to divide into two daughter cells. These events include the growth of the cell, duplication of its DNA (DNA re ...
progression.
Gene expression studies have suggested that Dock11 may have a role in the development of
pituitary
The pituitary gland or hypophysis is an endocrine gland in vertebrates. In humans, the pituitary gland is located at the base of the brain, protruding off the bottom of the hypothalamus. The pituitary gland and the hypothalamus control much of th ...
and
testicular
A testicle or testis ( testes) is the gonad in all male bilaterians, including humans, and is homologous to the ovary in females. Its primary functions are the production of sperm and the secretion of androgens, primarily testosterone.
The r ...
tumours.
Deficiency in humans
Hemizygous ''DOCK11'' mutations in humans are associated with early-onset and severe autoimmunity.
In eight male patients, from seven unrelated pedigrees, with hemizygous DOCK11 missense variants, a reduction in DOCK11 expression was observed. The patients presented with early-onset autoimmunity, including cytopenia, systemic lupus erythematosus, skin, and digestive manifestations. Platelets and lymphocytes exhibited abnormal ultrastructural morphology and spreading as well as impaired CDC42 activity. The patients' cells exhibited aberrant protrusions and abnormal migration speed in confined channels concomitant with altered actin polymerization during migration. A DOCK11 knock-down in monocytes-derived dendritic cells (MDDC) and in T cells from healthy controls, recapitulated these abnormal cellular phenotypes. Abnormal regulatory T cells (Tregs) phenotype with profoundly reduced FOXP3 and IKZF2 expression was also observed, consistent with the autoimmune features developed by the DOCK11-deficient patients. Moreover, the authors observed a reduced T cell proliferation and an impaired STAT5B phosphorylation upon IL2 stimulation of the patients' lymphocytes. DOCK11 deficiency is therefore a new X-linked immune-related
actinopathy leading to abnormal actin cytoskeleton remodeling, impaired CDC42 activity and STAT5 activation, and associated with early-onset autoimmunity.
References
Further reading
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