Dedicator of cytokinesis protein 4 (Dock4), is a large (~190 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 ''DOCK4'' 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-B 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. Dock4 activates the small G proteins

Rac RAC or Rac may refer to: Organizations * Radio Amateurs of Canada * RATCH-Australia Corporation, electricity generator * Refugee Action Collective (Victoria), Melbourne, Australia * Religious Action Center of Reform Judaism, US * Rent-A-Cent ...

and

Rap1 Rap1 (Ras-proximate-1 or Ras-related protein 1) is a small GTPase, which are small cytosolic proteins that act like cellular switches and are vital for effective signal transduction. There are two isoforms of the Rap1 protein, each encoded by ...

Discovery

Dock4 was discovered as a

gene product A gene product is the biochemical material, either RNA or protein, resulting from the 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 corre ...

which was disrupted during

tumour A neoplasm () is a type of abnormal and excessive growth of tissue (biology), tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tiss ...

progression in a murine cancer model-derived

osteosarcoma An osteosarcoma (OS) or osteogenic sarcoma (OGS) is a cancerous tumor in a bone. Specifically, it is an aggressive malignant neoplasm that arises from primitive transformed cells of mesenchyme, mesenchymal origin (and thus a sarcoma) and that exhi ...

cell line. Subsequent

Northern blot The northern blot, or RNA blot,Gilbert, S. F. (2000) Developmental Biology, 6th Ed. Sunderland MA, Sinauer Associates. is a technique used in molecular biology research to study gene expression by detection of RNA (or isolated mRNA) in a sample.Ke ...

analysis revealed high levels of Dock4 expression in

skeletal muscle Skeletal muscle (commonly referred to as muscle) is one of the three types of vertebrate muscle tissue, the others being cardiac muscle and smooth muscle. They are part of the somatic nervous system, voluntary muscular system and typically are a ...

prostate The prostate is an male accessory gland, accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found in all male mammals. It differs between species anatomically, chemica ...

and

ovary The ovary () is a gonad in the female reproductive system that produces ova; when released, an ovum travels through the fallopian tube/ oviduct into the uterus. There is an ovary on the left and the right side of the body. The ovaries are end ...

as well as lower levels in the

heart The heart is a muscular Organ (biology), organ found in humans and other animals. This organ pumps blood through the blood vessels. The heart and blood vessels together make the circulatory system. The pumped blood carries oxygen and nutrie ...

placenta The placenta (: placentas or placentae) is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas, and waste exchange between ...

and colon. A separate study has reported expression of a Dock4

splice variant Alternative splicing, alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to produce different splice variants. For example, some exons of a gene may be included ...

( Dock4-Ex49) in the brain,

inner ear The inner ear (internal ear, auris interna) is the innermost part of the vertebrate ear. In vertebrates, the inner ear is mainly responsible for sound detection and balance. In mammals, it consists of the bony labyrinth, a hollow cavity in the ...

and eye.

Structure and function

Dock4 is part of a large class of proteins (GEFs) which contribute to cellular signalling events by activating small G proteins. In their resting state G proteins are bound to

Guanosine diphosphate Guanosine diphosphate, abbreviated GDP, is a nucleoside diphosphate. It is an ester of pyrophosphoric acid with the nucleoside guanosine. GDP consists of a pyrophosphate group, a pentose sugar ribose, and the nucleobase guanine. GDP is the pr ...

(GDP) and their activation requires the dissociation of GDP and binding of

guanosine triphosphate Guanosine-5'-triphosphate (GTP) is a purine nucleoside triphosphate. It is one of the building blocks needed for the synthesis of RNA during the transcription process. Its structure is similar to that of the guanosine nucleoside, the only di ...

(GTP). GEFs activate G proteins by promoting this nucleotide exchange. The domain arrangement of Dock4 is largely equivalent to that of

Dock180 Dedicator of cytokinesis protein 1 (Dock1), also (DOCK180), is a large (~180 kDa) protein encoded in the human by the ''DOCK1'' gene, involved in intracellular signalling networks. It is the mammalian ortholog of the ''C. elegans'' protein CED ...

(the archetypal member of the

family) and other DOCK-A/B family members (35%

sequence identity 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. Align ...

with Dock180, 39% with Dock2 and 54% with Dock3). Dock4, however, contains a unique set of motifs at its

proline Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the p ...

-rich

C-terminus The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein Proteins are large biomolecules and macromolecules that comp ...

which include a Src-binding site that is shared with CED-5, the ''

C. elegans ''Caenorhabditis elegans'' () is a free-living transparent nematode about 1 mm in length that lives in temperate soil environments. It is the type species of its genus. The name is a blend of the Greek ''caeno-'' (recent), ''rhabditis'' ( ...

ortholog Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a speci ...

of mammalian DOCK proteins. Dock4 also 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 ...

(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 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 ...

Regulation of Dock4 activity

DOCK family proteins are inefficient at promoting nucleotide exchange on their own since they appear to adopt an autoinhibitory conformation in their resting state. The adaptor protein

ELMO Elmo is a Muppet character on the children's television show ''Sesame Street''. A furry red monster who speaks in a high-pitched falsetto voice and frequently refers to himself in the third person, he hosts the last full 15-minute segmen ...

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 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 ...

of ELMO and also involves an interaction between the

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 ...

SH3 domain The SRC Homology 3 Domain (or SH3 domain) is a small protein domain of about 60 amino acid residues. Initially, SH3 was described as a conserved sequence in the viral adaptor protein v-Crk. This domain is also present in the molecules of ph ...

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 (Ras homology Growth-related) (or ARGH) is a small (~21 kDa) monomeric GTP-binding protein (G protein), and is an important component of many intracellular signalling pathways. It is a member of the Rac subfamily of the Rho family of sma ...

and this has been shown to promote DOCK-dependent signalling by helping recruit the ELMO-DOCK

complex Complex commonly refers to: * Complexity, the behaviour of a system whose components interact in multiple ways so possible interactions are difficult to describe ** Complex system, a system composed of many components which may interact with each ...

to areas of high

substrate Substrate may refer to: Physical layers *Substrate (biology), the natural environment in which an organism lives, or the surface or medium on which an organism grows or is attached ** Substrate (aquatic environment), the earthy material that exi ...

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 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 ...

fibroblasts A fibroblast is a type of biological cell typically with a spindle shape that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibrobla ...

. In rat

hippocampal The hippocampus (: hippocampi; via Latin from Greek , 'seahorse'), also hippocampus proper, is a major component of the brain of humans and many other vertebrates. In the human brain the hippocampus, the dentate gyrus, and the subiculum ar ...

neurone A neuron (American English), neurone (British English), or nerve cell, is an excitable cell that fires electric signals called action potentials across a neural network in the nervous system. They are located in the nervous system and help to ...

s Dock4 forms a trimeric complex with ELMO2 and CrkII which is required for the normal development of

dendrite A dendrite (from Ancient Greek language, Greek δένδρον ''déndron'', "tree") or dendron is a branched cytoplasmic process that extends from a nerve cell that propagates the neurotransmission, electrochemical stimulation received from oth ...

s. More recently, a role has been described for Dock4 as part of the

Wnt signalling pathway In cellular biology, the Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt, pronounced "wint", is a portmanteau created from the ...

which regulates

cell proliferation Cell proliferation is the process by which ''a cell grows and divides to produce two daughter cells''. Cell proliferation leads to an exponential increase in cell number and is therefore a rapid mechanism of tissue growth. Cell proliferation ...

and migration. In this system Dock4 was reported to undergo

phosphorylation In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writ ...

Glycogen synthase kinase 3 Glycogen synthase kinase 3 (GSK-3) is a serine/threonine protein kinase that mediates the addition of phosphate molecules onto serine and threonine amino acid residues. First discovered in 1980 as a regulatory kinase for its namesake, glycogen ...

(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

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 ...

. 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 The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compos ...

and leads to the formation of membrane protrusions (e.g.

lamellipodia The lamellipodium (: lamellipodia) (from Latin ''lamella'', related to ', "thin sheet", and the Greek radical ''pod-'', "foot") is a cytoskeletal protein actin projection on the leading edge of the cell. It contains a quasi-two-dimensional act ...

) 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 Catenin beta-1, also known as β-catenin (''beta''-catenin), is a protein that in humans is encoded by the ''CTNNB1'' gene. β-Catenin is a dual function protein, involved in regulation and coordination of cell–cell adhesion and gene transcr ...

degradation complex".

Dock4 in cancer

Mutations in Dock4 have been described in a number of cancers. The exact mechanism and extent to which it regulates cancer-associated signalling pathways is poorly understood thus far although a mutation in Dock4 which affects its GEF specificity has been reported to promote detachment and invasion of cancer cells.

Discovery

Structure and function

Regulation of Dock4 activity

Signalling downstream of Dock4

Dock4 in cancer

References

Further reading