CTGF, also known as CCN2 or connective tissue growth factor,
is a
matricellular protein A matricellular protein is a dynamically expressed non-structural protein that is present in the extracellular matrix (ECM). Rather than serving as stable structural elements in the ECM, these proteins are rapidly turned over and have regulatory rol ...
of the CCN family of
extracellular matrix
In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide stru ...
-associated
heparin
Heparin, also known as unfractionated heparin (UFH), is a medication and naturally occurring glycosaminoglycan. Since heparins depend on the activity of antithrombin, they are considered anticoagulants. Specifically it is also used in the treatm ...
-binding proteins (see also
CCN intercellular signaling protein CCN proteins are a family of extracellular matrix (ECM)-associated proteins involved in intercellular signaling. Due to their dynamic role within the ECM they are considered matricellular proteins.
Background
The acronym CCN is derived from the fi ...
).
CTGF has important roles in many biological processes, including
cell adhesion
Cell adhesion is the process by which cells interact and attach to neighbouring cells through specialised molecules of the cell surface. This process can occur either through direct contact between cell surfaces such as cell junctions or indir ...
,
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 ...
,
proliferation,
angiogenesis
Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...
, skeletal development, and tissue wound repair, and is critically involved in fibrotic disease and several forms of
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
s.
Structure and binding partners
Members of the CCN protein family, including CTGF, are structurally characterized by having four conserved,
cysteine
Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile.
When present as a deprotonated catalytic residue, sometime ...
-rich domains. These domains are, from N- to C-termini, the insulin-like growth factor binding protein (
IGFBP
The insulin-like growth factor-binding protein (IGFBP) serves as a transport protein for insulin-like growth factor 1 (IGF-1).
Function
Approximately 98% of IGF-1 is always bound to one of six binding proteins (IGF-BP). IGFBP-3, the most abund ...
) domain, the von Willebrand type C repeats (
vWC) domain, the thrombospondin type 1 repeat (TSR) domain, and a C-terminal domain (CT) with a
cysteine knot
A cystine knot is a protein structural motif containing three disulfide bridges (formed from pairs of cysteine residues). The sections of polypeptide that occur between two of them form a loop through which a third disulfide bond passes, forming ...
motif. CTGF exerts its functions by binding to various cell surface receptors in a context-dependent manner, including
integrin receptor
Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, ...
s,
cell surface
heparan sulfate proteoglycans (HSPGs),
s,
and TrkA.
In addition, CTGF also binds growth factors and extracellular matrix proteins. The N-terminal half of CTGF interacts with
aggrecan
Aggrecan (ACAN), also known as cartilage-specific proteoglycan core protein (CSPCP) or chondroitin sulfate proteoglycan 1, is a protein that in humans is encoded by the ''ACAN'' gene. This gene is a member of the lectican (chondroitin sulfate prote ...
,
the TSR domain interacts with
VEGF
Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, ...
,
and the CT domain interacts with members of the TGF-β superfamily,
fibronectin
Fibronectin is a high- molecular weight (~500-~600 kDa) glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. Fibronectin also binds to other extracellular matrix proteins such as collage ...
,
perlecan
Perlecan (PLC) also known as basement membrane-specific heparan sulfate proteoglycan core protein (HSPG) or heparan sulfate proteoglycan 2 (HSPG2), is a protein that in humans is encoded by the ''HSPG2'' gene. The HSPG2 gene codes for a 4,391 amin ...
,
fibulin-1
FBLN1 is the gene encoding fibulin-1, an extracellular matrix and plasma protein.
Function
Fibulin-1 is a secreted glycoprotein that is found in association with extracellular matrix structures including fibronectin-containing fibers, elastin- ...
,
slit, and
mucin
Mucins () are a family of high molecular weight, heavily glycosylated proteins (glycoconjugates) produced by epithelial tissues in most animals. Mucins' key characteristic is their ability to form gels; therefore they are a key component in most ...
s.
Role in development
Knockout mice with the Ctgf gene disrupted die at birth due to respiratory stress as a result of severe
chondrodysplasia
Osteochondrodysplasia is a general term for a disorder of the development (dysplasia) of bone ("osteo") and cartilage ("chondro"). Osteochondrodysplasias are rare diseases. About 1 in 5,000 babies are born with some type of skeletal dysplasia. Non ...
.
Ctgf-null mice also show defects in angiogenesis, with impaired interaction between endothelial cells and pericytes and collagen IV deficiency in the endothelial basement membrane.
CTGF is also important for
pancreatic beta cell
Beta cells (β-cells) are a type of cell found in pancreatic islets that synthesize and secrete insulin and amylin. Beta cells make up 50–70% of the cells in human islets. In patients with Type 1 diabetes, beta-cell mass and function are dimini ...
development,
and is critical for normal
ovarian follicle
An ovarian follicle is a roughly spheroid cellular aggregation set found in the ovaries. It secretes hormones that influence stages of the menstrual cycle. At the time of puberty, women have approximately 200,000 to 300,000 follicles, each with th ...
development and
ovulation
Ovulation is the release of eggs from the ovaries. In women, this event occurs when the ovarian follicles rupture and release the secondary oocyte ovarian cells. After ovulation, during the luteal phase, the egg will be available to be fertilized ...
.
Clinical significance
CTGF is associated with
wound healing
Wound healing refers to a living organism's replacement of destroyed or damaged tissue by newly produced tissue.
In undamaged skin, the epidermis (surface, epithelial layer) and dermis (deeper, connective layer) form a protective barrier again ...
and virtually all
fibrotic
Fibrosis, also known as fibrotic scarring, is a pathological wound healing in which connective tissue replaces normal parenchymal tissue to the extent that it goes unchecked, leading to considerable tissue remodelling and the formation of perman ...
pathology.
It is thought that CTGF can cooperate with
TGF-β
Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other sign ...
to induce sustained
fibrosis
Fibrosis, also known as fibrotic scarring, is a pathological wound healing in which connective tissue replaces normal parenchymal tissue to the extent that it goes unchecked, leading to considerable tissue remodelling and the formation of perma ...
and to exacerbate extracellular matrix production in association other fibrosis-inducing conditions.
Overexpression of CTGF in fibroblasts promotes fibrosis in the dermis, kidney, and lung,
and deletion of Ctgf in fibroblasts and smooth muscle cells greatly reduces
bleomycin
-13- (1''H''-imidazol-5-yl)methyl9-hydroxy-5- 1''R'')-1-hydroxyethyl8,10-dimethyl-4,7,12,15-tetraoxo-3,6,11,14-tetraazapentadec-1-yl}-2,4'-bi-1,3-thiazol-4-yl)carbonyl]amino}propyl)(dimethyl)sulfonium
, chemical_formula =
, C=55 , H=84 , N=1 ...
-induced skin fibrosis.
In addition to fibrosis, aberrant CTGF expression is also associated with many types of malignancies,
diabetic nephropathy
Diabetic nephropathy, also known as diabetic kidney disease, is the chronic loss of kidney function occurring in those with diabetes mellitus. Diabetic nephropathy is the leading causes of chronic kidney disease (CKD) and end-stage renal disease ...
and
retinopathy
Retinopathy is any damage to the retina of the eyes, which may cause vision impairment. Retinopathy often refers to retinal vascular disease, or damage to the retina caused by abnormal blood flow. Age-related macular degeneration is technically inc ...
, arthritis, and cardiovascular diseases. Several clinical trials are now ongoing that investigate the therapeutic value of targeting CTGF in fibrosis, diabetic nephropathy, and
pancreatic cancer
Pancreatic cancer arises when cell (biology), cells in the pancreas, a glandular organ behind the stomach, begin to multiply out of control and form a Neoplasm, mass. These cancerous cells have the malignant, ability to invade other parts of t ...
.
CTGF (CCN2) has recently been implicated in mood disorders, notably in the postpartum period; these effects may be mediated by its effects on myelination
See also
*
Ctgf/hcs24 CAESAR
*
CYR61
Cysteine-rich angiogenic inducer 61 (CYR61) or CCN family member 1 (CCN1), is a matricellular protein that in humans is encoded by the ''CYR61'' gene.
CYR61 is a secreted, extracellular matrix (ECM)-associated signaling protein of the CCN family ...
(CCN1)
References
External links
*
{{Growth factor receptor modulators
Growth factors
CCN proteins