CTGF, also known as CCN2 or connective tissue growth factor, [5] [6] is a matricellular protein of the CCN family of extracellular matrix-associated heparin-binding proteins (see also CCN intercellular signaling protein). [7] [8] [9] CTGF has important roles in many biological processes, including cell adhesion, migration, proliferation, angiogenesis, skeletal development, and tissue wound repair, and is critically involved in fibrotic disease and several forms of cancers. [5] [6] [10]
Members of the CCN protein family, including CTGF, are structurally characterized by having four conserved, cysteine-rich domains. These domains are, from N- to C-termini, the insulin-like growth factor binding protein (IGFBP) 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 motif. CTGF exerts its functions by binding to various cell surface receptors in a context-dependent manner, including integrin receptors, [11] [12] [13] cell surface heparan sulfate proteoglycans (HSPGs), [14] LRPs, [15] and TrkA. [16] In addition, CTGF also binds growth factors and extracellular matrix proteins. The N-terminal half of CTGF interacts with aggrecan, [17] the TSR domain interacts with VEGF, [18] and the CT domain interacts with members of the TGF-β superfamily, fibronectin, perlecan, fibulin-1, slit, and mucins. [5] [6]
Knockout mice with the Ctgf gene disrupted die at birth due to respiratory stress as a result of severe chondrodysplasia. [19] 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. [20] CTGF is also important for pancreatic beta cell development, [21] and is critical for normal ovarian follicle development and ovulation. [22]
CTGF is associated with wound healing and virtually all fibrotic pathology. [9] [23] It is thought that CTGF can cooperate with TGF-β to induce sustained fibrosis [24] and to exacerbate extracellular matrix production in association other fibrosis-inducing conditions. [23] Overexpression of CTGF in fibroblasts promotes fibrosis in the dermis, kidney, and lung, [25] and deletion of Ctgf in fibroblasts and smooth muscle cells greatly reduces bleomycin-induced skin fibrosis. [26]
In addition to fibrosis, aberrant CTGF expression is also associated with many types of malignancies, diabetic nephropathy [27] and retinopathy, 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. [5]
CTGF (CCN2) has recently been implicated in mood disorders, notably in the postpartum period; these effects may be mediated by its effects on myelination [28]
Integrins are transmembrane receptors that help 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, organization of the intracellular cytoskeleton, and movement of new receptors to the cell membrane. The presence of integrins allows rapid and flexible responses to events at the cell surface.
Fibronectin is a high-molecular weight glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. It is approved for marketing as a topical solution in India by Central Drugs Standard Control organization in 2020 under the brand name FIBREGA for chronic wounds. Fibronectin also binds to other extracellular matrix proteins such as collagen, fibrin, and heparan sulfate proteoglycans.
In biology, the extracellular matrix (ECM), is a network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide structural and biochemical support to surrounding cells. Because multicellularity evolved independently in different multicellular lineages, the composition of ECM varies between multicellular structures; however, cell adhesion, cell-to-cell communication and differentiation are common functions of the ECM.
Cell adhesion molecules (CAMs) are a subset of cell surface proteins that are involved in the binding of cells with other cells or with the extracellular matrix (ECM), in a process called cell adhesion. In essence, CAMs help cells stick to each other and to their surroundings. CAMs are crucial components in maintaining tissue structure and function. In fully developed animals, these molecules play an integral role in generating force and movement and consequently ensuring that organs are able to execute their functions normally. In addition to serving as "molecular glue", CAMs play important roles in the cellular mechanisms of growth, contact inhibition, and apoptosis. Aberrant expression of CAMs may result in a wide range of pathologies, ranging from frostbite to cancer.
Endostatin is a naturally occurring, 20-kDa C-terminal fragment derived from type XVIII collagen. It is reported to serve as an anti-angiogenic agent, similar to angiostatin and thrombospondin.
Endoglin (ENG) is a type I membrane glycoprotein located on cell surfaces and is part of the TGF beta receptor complex. It is also commonly referred to as CD105, END, FLJ41744, HHT1, ORW and ORW1. It has a crucial role in angiogenesis, therefore, making it an important protein for tumor growth, survival and metastasis of cancer cells to other locations in the body.
Thrombospondin 1, abbreviated as THBS1, is a protein that in humans is encoded by the THBS1 gene.
72 kDa type IV collagenase also known as matrix metalloproteinase-2 (MMP-2) and gelatinase A is an enzyme that in humans is encoded by the MMP2 gene. The MMP2 gene is located on chromosome 16 at position 12.2.
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.
Tenascin C (TN-C) is a glycoprotein that in humans is encoded by the TNC gene. It is expressed in the extracellular matrix of various tissues during development, disease or injury, and in restricted neurogenic areas of the central nervous system. Tenascin-C is the founding member of the tenascin protein family. In the embryo it is made by migrating cells like the neural crest; it is also abundant in developing tendons, bone and cartilage.
NOV also known as CCN3 is a matricellular protein that in humans is encoded by the NOV gene.
WNT1-inducible-signaling pathway protein 1 (WISP-1), also known as CCN4, is a matricellular protein that in humans is encoded by the WISP1 gene.
WNT1-inducible-signaling pathway protein 3 is a matricellular protein that in humans is encoded by the WISP3 gene.
WNT1-inducible-signaling pathway protein 2, or WISP-2 is a matricellular protein that in humans is encoded by the WISP2 gene.
Integrin alpha-9 is a protein that in humans is encoded by the ITGA9 gene. Cytogenetic location: 3p22.2
Angiogenesis is the process of forming new blood vessels from existing blood vessels, formed in vasculogenesis. It is a highly complex process involving extensive interplay between cells, soluble factors, and the extracellular matrix (ECM). Angiogenesis is critical during normal physiological development, but it also occurs in adults during inflammation, wound healing, ischemia, and in pathological conditions such as rheumatoid arthritis, hemangioma, and tumor growth. Proteolysis has been indicated as one of the first and most sustained activities involved in the formation of new blood vessels. Numerous proteases including matrix metalloproteinases (MMPs), a disintegrin and metalloproteinase domain (ADAM), a disintegrin and metalloproteinase domain with throbospondin motifs (ADAMTS), and cysteine and serine proteases are involved in angiogenesis. This article focuses on the important and diverse roles that these proteases play in the regulation of angiogenesis.
Transforming growth factor beta (TGF-β) is a potent cell regulatory polypeptide homodimer of 25kD. It is a multifunctional signaling molecule with more than 40 related family members. TGF-β plays a role in a wide array of cellular processes including early embryonic development, cell growth, differentiation, motility, and apoptosis.
Von Willebrand factor, type C is a protein domain is found in various blood plasma proteins: complement factors B, C2, CR3 and CR4; the integrins (I-domains); collagen types VI, VII, XII and XIV; and other extracellular proteins.
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.
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 roles. They characteristically contain binding sites for ECM structural proteins and cell surface receptors, and may sequester and modulate activities of specific growth factors.
