Dock4, (
Dedicator
of
cyto
kinesis 4) 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
A dock (from Dutch language, Dutch ''dok'') is the area of water between or next 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) or such structures themselves. The ex ...
family of
guanine nucleotide exchange factors (GEFs) which function as activators of small
G proteins. 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-Center, ...
and
Rap1.
Discovery
Dock4 was discovered as a
gene product 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
Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...
,
prostate and
ovary
The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the body. ...
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
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 (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
Dock180, (Dedicator of cytokinesis) also known as DOCK1, is a large (~180 kDa) protein involved in intracellular signalling networks. It is the mammalian ortholog of the ''C. elegans'' protein CED-5 and belongs to the DOCK family of Guanine nucl ...
(the archetypal member of the
DOCK
A dock (from Dutch language, Dutch ''dok'') is the area of water between or next 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) or such structures themselves. The ex ...
family) and other DOCK-A/B family members (35%
sequence identity with Dock180, 39% with
Dock2
Dock2 (Dedicator of cytokinesis 2), also known as DOCK2, is a large (~180 kDa) protein involved in intracellular Cell signalling, signalling networks. It is a member of the DOCK-A subfamily of the DOCK (protein), DOCK family of guanine nucleotide ...
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 prot ...
-rich
C-terminus
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
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'' (r ...
''
ortholog 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 ...
(also known as Docker2 or CZH2) which is conserved among DOCK family proteins and mediates GEF-dependent functions, 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 ...
(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 (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...
.
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 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
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 ami ...
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
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 (locomotion), the surface over which an organism lo ...
availability (usually the plasma membrane).
The C-terminus of DOCK proteins interacts with another adaptor protein,
Crk
Adapter molecule crk also known as proto-oncogene c-Crk is a protein that in humans is encoded by the ''CRK'' gene.
The CRK protein participates in the Reelin signaling cascade downstream of DAB1.
Function
Adapter molecule crk is a member of ...
.
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
dendrites.
More recently, a role has been described for Dock4 as part of the
Wnt signalling pathway
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 is a portmanteau created from the names Wingless and Int-1. Wnt signaling p ...
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 re ...
and migration. In this system Dock4 was reported to undergo
phosphorylation
In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
by
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 s ...
(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.
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
The lamellipodium (plural 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 ...
) 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".
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.
References
Further reading
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