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CTGF (connective tissue growth factor)

Written2007-07Satoshi Kubota, Masaharu Takigawa
Department of Biochemistry, Molecular Dentistry Okayama University Graduate School of Medicine, Dentistry, Pharmaceutical Sciences Dean, Okayama University Dental School 2-5-1, Shikata-cho, Okayama, 700-8525, Japan

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Alias (NCBI)CCN2
LocusID (NCBI) 1490
Atlas_Id 40192
Location 6q23.2  [Link to chromosome band 6q23]
Location_base_pair Starts at and ends at bp from pter
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
CTGF (6q23.2)::RPL6 (12q24.13)GPX7 (1p32.3)::CTGF (6q23.2)KLHDC4 (16q24.2)::CTGF (6q23.2)
Note CCN family protein 2/connective tissue growth factor (CCN2/CTGF) was initially identified in the culture supernatant of vascular endothelial cells. Subsequently, the CCN2/CTGF gene has been classified as a representative member of the CCN gene family that is an acronym of the original names of the 3 early members, Cyr61, CTGF and NOV. The mammalian genome contains 6 functional CCN family members, which were renamed based on the proposal of a unified nomenclature. CCN2/CTGF displays multiple functions via interaction with a variety of other molecules. It is important to note that CCN2/CTGF induces the development and regeneration of mesenchymal tissues including bone, cartilage and blood vessels.


  Structure of human CCN2/CTGF and its mRNA. Abbreviations S, I, V, T, and C denote the coding regions for the signal peptide, IGFBP module, VWC module, TSP1 module and CT module, respectively.
Description Unlike the other CCN family members, the CCN2/CTGF gene is conserved among all of the vertebrates and several invertebrates.
In Drosophila melanogaster, only one gene is designated as ccn, which is thought to have evolved from a prototypic CCN2/CTGF gene. Therefore, CCN2/CTGF may be regarded evolutionarily as an oldest gene in the CCN family. Consistent with such findings, human CCN2/CTGF gene is also quite compact. The total transcribed sequence is as short as 3.2 kb, and contains 4 intronic sequences of less than 400 bp.
Transcription The mature mRNA, 2.3 kb in length, is formed by connecting 5 exons encoding a signal peptide, an IGFBP module, a VWC module, a TSP1 module and CT module in the order. The last exon yields a long 3'-untranslated region of more than1.0 kb on the mRNA, which contains the critical elements for post-transcriptional regulation. The proximal promoter area upstream of the transcription initiation site is known to contain several enhancer elements that are critical for transcriptional regulation.


  Interaction of each module in CCN2/CTGF with other growth factors.
Description The CCN2/CTGF is composed of 4 distinct modules:
  • the N-terminal signal peptide for secretion;
  • insulin-like growth factor binding protein-like (IGFBP) module,
  • von Willebrand factor type-C repeat (VWC) module,
  • thrombospondin type 1 repeat (TSP1) module and
  • the C-terminal cystine knot (CT) module.
    This is consistent with other CCN family proteins. Because of this unique structure, the 6 CCN2/CTGF-related proteins are thought to form a distinct protein class which is distinct from the IGFBP family, despite the involvement of IGFBP module. The involvement of cysteine residues that are also conserved among the CCN family members is a prominent structural characteristic. All of the 4 modules are highly interactive with other biomolecules including growth factors, cell-surface receptor molecules and extracellular matrix components. In addition, the tetramodular construction of these modules provides the structural basis for the multiple functionality of CCN2/CTGF, which is described in another section.
  • Expression CCN2/CTGF is differentially expressed in certain tissues and organs, particularly in the cardiovascular, gonadal, renal and skeletal systems, during development of vertebrates. The cell population that expresses the CCN2/CTGF gene is highly restricted in each tissue; for example, this factor is produced in cartilage primarily by pre-hypertrophic and hypertrophic chondrocytes, in fact, it was previously referred to as hypertrophic chondrocyte-specific protein 24 (Hcs24).
    Localisation In addition to the tissues containing the cells which express this protein described above, CCN2/CTGF is abundantly present in platelets, although its origin is still unknown.
    Function Under the multiple interactions with specific molecular counterparts, CCN2/CTGF conducts the local information network of extracellular signaling molecules and exerts multiple functions, depending upon the microenvironmental conditions. Indeed, CCN2/CTGF promotes both proliferation and differentiation of mesenchymal stem cells, chondrocytes, osteoblasts, periodontal ligament cells, fibroblasts and vascular endothelial cells in vitro. As a result of these effects, this factor enhances wound healing and tissue regeneration of cartilage and bone.
    Homology CCN2/CTGF is structurally homologous to the other 5 CCN family members. The cysteine residues are highly conserved among the members.


    Germinal Until today, no association between mutations in the CCN2/CTGF gene and specific genetic diseases has been described. In mouse models, deletion of both CCN2/CTGF alleles results in severe skeletal malformation, leading to respiratory failure upon delivery. Histological and cell biological analysis revealed that the endochondral ossification process was specifically affected by the CCN2/CTGF deletion, particularly at the final stage that is supported by blood vessel invasion. However, no apparent phenotypic complication has been observed in CCN2/CTGF (-/+) heterozygous mice.
    Somatic At present, nearly 30 SNPs have been described in the NCBI database. Among the SNPs, 35.7% and 39.3% of the total cases have been reported to exist outside of the transcribed area and in the areas of untranslated regions (UTRs) and introns, respectively. Mutation/variation in the open reading frame (ORF) was found in 25% of the total. Missense mutation occurred at a frequency of 42.7 %, whereas the other cases were silent. Excluding the UTRs, the IGFBP-encoding 2nd exon has been a hot spot of mutation and variation (57.1% of the one within ORF). In a single case, an African population was analyzed to compute the actual frequency. This demonstrated that the frequency of a mutation in the 3rd exon, which caused a missense change of amino acid 118 from asparagine to serine by an A to G transition, was 1.3%. Including these cases, no association of a SNP in the CCN2/CTGF gene with any particular human disorder has been described until now.

    Implicated in

    Entity Cancers
    Oncogenesis Although the CCN2/CTGF expression is observed in a number of different types of malignant neoplasm, the role of CCN2/CTGF in oncogenesis and its association with malignant phenotypes are quite controversial.
    According to a previous study, a positive correlation was observed between the level of CCN2/CTGF expression and the degree of malignancy in breast cancer and colorectal cancer cases. These findings are consistent with other recent reports describing the contribution of CCN/CTGF in developing bone metastasis of breast cancers. The ability to promote metastasis can be partially ascribed to the angiogenic activity of CCN2/CTGF.
    However, over expression of CCN2/CTGF in cells of the same origin is reported to induce apoptosis. Furthermore, in chondrosarcoma cases, patients with higher CCN2/CTGF expression in tumors survived longer than those with lower CCN2/CTGF expression. These findings are consistent with the observation that overexpression of CCN2/CTGF results in benign conversion of the phenotype in oral squamous carcinoma cells and induces cell cycle arrest in fibroblasts. The observations above suggest that CCN2/CTGF produced by tumor cells may exert paracrine angiogenic and autocrine/intracrine anti-proliferative effects in solid tumors.
    Entity Fibrotic disorders.
    Disease Since its initial discovery, CCN2/CTGF has been widely known as a profibrotic factor that is involved in a variety of fibrotic disorders.
    CCN2/CTGF is associated with systemic sclerosis, keloids, pulmonary fibrosis, diabetic renal fibrosis, liver cirrhosis, pancreatic fibrosis, atherosclerosis, myocardial fibrosis, biliary atresia and cataracts.
    Since CCN2/CTGF has a positive role in wound healing and mesenchymal tissue regeneration, the fibrotic changes observed in those diseases may be regarded as a result of dysregulated regeneration of corresponding tissues.
    Prognosis Fibrotic changes are usually irreversible; however, antibody-mediated molecular therapeutics against CCN2/CTGF is currently being developed to prevent the development of fibrotic lesions.


    Connective-tissue growth factor (CTGF) modulates cell signalling by BMP and TGF-beta.
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    Nature cell biology. 2002 ; 4 (8) : 599-604.
    PMID 12134160
    Effect of connective tissue growth factor (CCN2/CTGF) on proliferation and differentiation of mouse periodontal ligament-derived cells.
    Asano M, Kubota S, Nakanishi T, Nishida T, Yamaai T, Yosimichi G, Ohyama K, Sugimoto T, Murayama Y, Takigawa M
    Cell communication and signaling : CCS. 2005 ; 3 : page 11.
    PMID 16207372
    Fisp12/mouse connective tissue growth factor mediates endothelial cell adhesion and migration through integrin alphavbeta3, promotes endothelial cell survival, and induces angiogenesis in vivo.
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    Molecular and cellular biology. 1999 ; 19 (4) : 2958-2966.
    PMID 10082563
    Connective tissue growth factor: a cysteine-rich mitogen secreted by human vascular endothelial cells is related to the SRC-induced immediate early gene product CEF-10.
    Bradham DM, Igarashi A, Potter RL, Grotendorst GR
    The Journal of cell biology. 1991 ; 114 (6) : 1285-1294.
    PMID 1654338
    Activated human platelets release connective tissue growth factor.
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    Thrombosis and haemostasis. 2004 ; 91 (4) : 755-760.
    PMID 15045137
    A novel cis-element that enhances connective tissue growth factor gene expression in chondrocytic cells.
    Eguchi T, Kubota S, Kondo S, Kuboki T, Yatani H, Takigawa M
    Biochemical and biophysical research communications. 2002 ; 295 (2) : 445-451.
    PMID 12150969
    Connective tissue growth factor (CCN2) induces adhesion of rat activated hepatic stellate cells by binding of its C-terminal domain to integrin alpha(v)beta(3) and heparan sulfate proteoglycan.
    Gao R, Brigstock DR
    The Journal of biological chemistry. 2004 ; 279 (10) : 8848-8855.
    PMID 14684735
    A novel transforming growth factor beta response element controls the expression of the connective tissue growth factor gene.
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    PMID 9052988
    Connective tissue growth factor is directly related to liver fibrosis.
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    Hepato-gastroenterology. 2002 ; 49 (43) : 133-135.
    PMID 11941937
    Connective tissue growth factor induces apoptosis in human breast cancer cell line MCF-7.
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    The Journal of biological chemistry. 1999 ; 274 (52) : 37461-37466.
    PMID 10601320
    CT domain of CCN2/CTGF directly interacts with fibronectin and enhances cell adhesion of chondrocytes through integrin alpha5beta1.
    Hoshijima M, Hattori T, Inoue M, Araki D, Hanagata H, Miyauchi A, Takigawa M
    FEBS letters. 2006 ; 580 (5) : 1376-1382.
    PMID 16457822
    Connective tissue growth factor gene expression in tissue sections from localized scleroderma, keloid, and other fibrotic skin disorders.
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    PMID 8618012
    Connective tissue growth factor binds vascular endothelial growth factor (VEGF) and inhibits VEGF-induced angiogenesis.
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    The FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2002 ; 16 (2) : 219-221.
    PMID 11744618
    Expression of connective tissue growth factor in human renal fibrosis.
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    Kidney international. 1998 ; 53 (4) : 853-861.
    PMID 9551391
    Connective tissue growth factor coordinates chondrogenesis and angiogenesis during skeletal development.
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    PMID 12736220
    Novel intracellular effects of human connective tissue growth factor expressed in Cos-7 cells.
    Kubota S, Hattori T, Shimo T, Nakanishi T, Takigawa M
    FEBS letters. 2000 ; 474 (1) : 58-62.
    PMID 10828451
    Abundant retention and release of connective tissue growth factor (CTGF/CCN2) by platelets.
    Kubota S, Kawata K, Yanagita T, Doi H, Kitoh T, Takigawa M
    Journal of biochemistry. 2004 ; 136 (3) : 279-282.
    PMID 15598883
    Identification of an RNA element that confers post-transcriptional repression of connective tissue growth factor/hypertrophic chondrocyte specific 24 (ctgf/hcs24) gene: similarities to retroviral RNA-protein interactions.
    Kubota S, Kondo S, Eguchi T, Hattori T, Nakanishi T, Pomerantz RJ, Takigawa M
    Oncogene. 2000 ; 19 (41) : 4773-4786.
    PMID 11032028
    Role of CCN2/CTGF/Hcs24 in bone growth.
    Kubota S, Takigawa M
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    PMID 17280894
    Connective tissue growth factor gene regulation. Requirements for its induction by transforming growth factor-beta 2 in fibroblasts.
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    The Journal of biological chemistry. 2003 ; 278 (15) : 13008-13015.
    PMID 12571253
    Suppressive effect of overexpressed connective tissue growth factor on tumor cell growth in a human oral squamous cell carcinoma-derived cell line.
    Moritani NH, Kubota S, Nishida T, Kawaki H, Kondo S, Sugahara T, Takigawa M
    Cancer letters. 2003 ; 192 (2) : 205-214.
    PMID 12668285
    Effects of CTGF/Hcs24, a product of a hypertrophic chondrocyte-specific gene, on the proliferation and differentiation of chondrocytes in culture.
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    Endocrinology. 2000 ; 141 (1) : 264-273.
    PMID 10614647
    CTGF/Hcs24, a hypertrophic chondrocyte-specific gene product, stimulates proliferation and differentiation, but not hypertrophy of cultured articular chondrocytes.
    Nishida T, Kubota S, Nakanishi T, Kuboki T, Yosimichi G, Kondo S, Takigawa M
    Journal of cellular physiology. 2002 ; 192 (1) : 55-63.
    PMID 12115736
    CCN proteins: multifunctional signalling regulators.
    Perbal B
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    PMID 14723997
    Expression of connective tissue growth factor in cartilaginous tumors.
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    Cancer. 2000 ; 89 (7) : 1466-1473.
    PMID 11013359
    Pathogenic role of connective tissue growth factor (CTGF/CCN2) in osteolytic metastasis of breast cancer.
    Shimo T, Kubota S, Yoshioka N, Ibaragi S, Isowa S, Eguchi T, Sasaki A, Takigawa M
    Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2006 ; 21 (7) : 1045-1059.
    PMID 16813525
    Connective tissue growth factor induces the proliferation, migration, and tube formation of vascular endothelial cells in vitro, and angiogenesis in vivo.
    Shimo T, Nakanishi T, Nishida T, Asano M, Kanyama M, Kuboki T, Tamatani T, Tezuka K, Takemura M, Matsumura T, Takigawa M
    Journal of biochemistry. 1999 ; 126 (1) : 137-145.
    PMID 10393331
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    Drug news & perspectives. 2003 ; 16 (1) : 11-21.
    PMID 12682668
    Role of CTGF/HCS24/ecogenin in skeletal growth control.
    Takigawa M, Nakanishi T, Kubota S, Nishida T
    Journal of cellular physiology. 2003 ; 194 (3) : 256-266.
    PMID 12548546
    Establishment of the enzyme-linked immunosorbent assay for connective tissue growth factor (CTGF) and its detection in the sera of biliary atresia.
    Tamatani T, Kobayashi H, Tezuka K, Sakamoto S, Suzuki K, Nakanishi T, Takigawa M, Miyano T
    Biochemical and biophysical research communications. 1998 ; 251 (3) : 748-752.
    PMID 9790981
    Connective tissue growth factor CCN2 interacts with and activates the tyrosine kinase receptor TrkA.
    Wahab NA, Weston BS, Mason RM
    Journal of the American Society of Nephrology : JASN. 2005 ; 16 (2) : 340-351.
    PMID 15601748
    Elevated levels of connective tissue growth factor, WISP-1, and CYR61 in primary breast cancers associated with more advanced features.
    Xie D, Nakachi K, Wang H, Elashoff R, Koeffler HP
    Cancer research. 2001 ; 61 (24) : 8917-8923.
    PMID 11751417
    Connective tissue growth factor is a regulator for fibrosis in human chronic pancreatitis.
    di Mola FF, Friess H, Martignoni ME, Di Sebastiano P, Zimmermann A, Innocenti P, Graber H, Gold LI, Korc M, Büchler MW
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    PMID 10400038


    This paper should be referenced as such :
    Kubota, S ; Takigawa, M
    CTGF (connective tissue growth factor)
    Atlas Genet Cytogenet Oncol Haematol. 2008;12(1):35-38.
    Free journal version : [ pdf ]   [ DOI ]

    External links

    Genomic and cartography
    Gene and transcription
    RefSeq transcript (Entrez)
    BioGPS (Tissue expression)1490
    Protein : pattern, domain, 3D structure
    Domain families : Pfam (Sanger)
    Domain families : Pfam (NCBI)
    Protein Interaction databases
    Ontologies - Pathways
    REVIEW articlesautomatic search in PubMed
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