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FLASH GENE
Symbol CTGF contributors: mct/npt/pgu - updated : 15-03-2016
HGNC name connective tissue growth factor
HGNC id 2500
Location 6q23.2      Physical location : 132.269.318 - 132.272.518
Synonym name
  • insuline-like growth factor-binding protein 8
  • hypertrophic chondrocyte-specific protein 24
  • connective tissue growth factor/cysteine-rich 61/nephroblastoma overexpressed 2
    • Synonym symbol(s) IGFBP8, IGFBPR2, CCN2, NOV2, HCS24, MGC102839
    DNA
    TYPE functioning gene
    STRUCTURE 3.20 kb     5 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter
    motif repetitive sequence   other
    text structure
  • TGFB responsive element
  • CTGF promoter was activated by overexpressed MMP3
    • MAPPING cloned Y linked N status provisional
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    5 - 2358 38 349 - 2008 19378419
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveliver     Homo sapiens
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Connectivebone  highly
    Connectivecartilage  specific
    cells
    SystemCellPubmedSpeciesStageRna symbol
     chondrocyte
    cell lineage
    cell lines tumor associated endothelial cells, malignant prostatic cells
    fluid/secretion
    at STAGE
    Text
  • highly in developing cartilage, in the pre-hypertrophic zone of the growth plate
  • detected mostly in tissues of compact cell organization such as the notochord, somites, cartilage and tooth bud
    • PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a N terminal IGFBP motif
  • a central domain lacking cysteine residues
  • invariant cysteine residues : 11 N terminal, 6 C terminal
  • an IGFBP [IGF (insulin-like growth factor)-binding protein-like] and/or VWC (von Willebrand factor type C) domains that had a direct interaction with aggrecan
  • thrombospondin type 1 domain
  • one C terminal cystine knot domain
    • HOMOLOGY
    interspecies homolog to murine Ctgf
    intraspecies homolog to NOV
    Homologene
    FAMILY
  • connective tissue growth factor (CCN) family, of matricellular proteins
    • CATEGORY protooncogene , signaling growth factor
    SUBCELLULAR LOCALIZATION extracellular
        plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,Golgi
    intracellular,cytoplasm,cytosolic
    basic FUNCTION
  • cysteine-rich protein promoting proliferation and differentiation of chondrocytes and mediating cell adhesion and growth for both fibroblasts and endothelial cells
  • promote both the proliferation and differentiation of chondrocytes, which actions are mediated by ERK and MAPK14
  • playing a direct role in cartilage and bone formation
  • required for the production of proteoglycans
  • having an essential role for normal skeletal development
  • enhanced the mRNA expressions and protein release of fractalkine, CCL2 and CCL5
  • promotes cellular functions, including proliferation and differentiation of chondrocytes, osteoblasts, and endothelial cells
  • induces production of fractalkine, CCL2 and CCL5 via ERK1/2 and PI3-K/PKB/NF-kappaB-dependent signal pathway mediated by cell surface heparin sulfate proteoglycans and the tyrosine kinase receptor TrkA in human mesangial cells
  • CTGF and WISP2, during cardiac remodeling can potentially play opposing roles during the development of cardiac hypertrophy and fibrosis
  • multifunctional regulator protein of cell behavior, that may regulate many biological processes such as cell attachment, migration, survival, proliferation, differentiation and matrix production
  • specifically induced the synthesis of decorin, suggesting a mechanism of autoregulation
  • induces the synthesis of its negative regulator decorin
  • has a chemotactic property, increasing cell aggregation around its source
  • could induce the expression of adhesive molecules, rather than itself acting as an adhesive molecule
  • MAPK8 mediates the expression of CTGF and corneal scarring in corneal wound healing
  • acts as an anabolic growth factor to regulate osteoblast differentiation and function
  • important mediator during development of glomerular and tubulointerstitial fibrosis in progressive kidney disease
  • plays a critical role in the development of mesenchymal tissues such as cartilage and bone
  • a matricellular-secreted protein involved in complex processes such as wound healing, angiogenesis, fibrosis and metastasis, in the regulation of cell proliferation, migration and extracellular matrix remodeling
  • may be a key regulator of fibrosis during maladaptive remodeling and progression to heart failure (HF)
  • is a downstream target of the TGFB signaling pathway in palatogenesis
  • regulates proliferation as a mediator of the canonical pathway of TGFB signaling during palatogenesis
  • regulated human keratinocyte migration through activation of the RAS-mitogen-activated protein kinase kinase-ERK signal transduction pathway
  • TGFB2, GREM1 and connective tissue growth factor (CTGF) are known to play important roles in the induction of epithelial mesenchymal transition (EMT) and extracellular matrix (ECM) synthesis
  • acts as an anabolic growth factor to regulate osteoblast differentiation and function
    • CELLULAR PROCESS cell life, differentiation
    cell life, proliferation/growth
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • potential target of WNT and BMP signaling (regulated by WNT and bone morphogenetic proteins signaling in osteoblast differentiation of mesenchymal stem cells)
  • interacting with PTK2 (a reduction PTK2 signaling is a critical feature permitting chondrogenic differentiation and CCN2 operates downstream of this loss to promote chondrogenesis)
  • acting as a promoter of chondrocyte differentiation
  • required for the regulation of cartilage and subsequent events, but also for the normal intramembranous bone development
  • binds VEGF (vascular endothelial growth factor) and inhibits its angiogenic effect
  • binds via its IGFBP and VWC domains to the G3 domain of aggrecan (ACAN)and is involved in the induction of aggrecan synthesis sheds new light on the role of CCN2/CTGF as a modifier of ECM structure and composition
  • CTGF is a novel substrate of ADAM28
  • PROK1 regulates CTGF expression via the Gq, phospholipase C (PLC), cSrc, epidermal growth factor receptor (EGFR), mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) kinase pathway activation
  • RRAD inhibits CTGF expression through binding with CEBPD, thus regulating ECM (extracellular matrix) production in the heart
  • interacting with DLL1 (indirect upregulation of CTGF expression by DLL1 is likely due to the ability of Dll1icd to increase Wnt signaling, a pathway that targets CTGF)
  • GREM1 also induces both TGFB2 and CTGF, which can act downstream to mediate some of these ECM changes in trabecular meshwork (TM)cells
  • LRP1 mediates the transcytosis of CTGF, which might be a crucial event that determines the distribution of CTGF in cartilage
  • ETS1 is essential for connective tissue growth factor (CTGF/CCN2) induction by TGFB1 in osteoblasts
  • OSM is a potent inhibitor of TGFB1-induced CTGF expression in human proximal tubular cells (PTC)
  • in human PTC the inhibitory action of OSM on basal and TGFB1-induced CTGF mRNA expression is primarily mediated by STAT3
  • early TGFB1-stimulated expression of CTGF mRNA in human PTC is at least partially mediated by SMAD3, while OSM inhibitory effect on basal and TGFB1-induced CTGF expression is mainly driven by STAT3
  • CTGF and FGF2 had a collaborative effect on the phosphorylation of ERK and the differentiation of osteoblastic cells
  • biological significance of the binding of CTGF to FGFR2 in bone metabolism
  • involvement of STAT3 activation in modulating CTGF production upon TGFB challenge in activated hepatic stellate cells (HSCs)
  • direct interaction of CTGF and FGF1, suggesting the co-presence of these molecules in the cartilage microenvironment
  • CTGF significantly bound to TNFRSF11B, which is a decoy receptor of TNFSF11
  • CTGF canceled the inhibitory effect of TNFRSF11B on osteoclast differentiation
  • interaction of MZF1 with the CTGF and NOV promoters in several cell types
  • AFAP1 is an essential downstream signaling component of TGFB1 for SRC activation, CTGF induction and collagen XIIa in osteoblasts
    • cell & other
    REGULATION
    activated by WNT3A and GDF2 at the early stage of osteogenic differentiation, which may regulate the proliferation and recruitment of osteoprogenitor cells
    induced by the WNT signaling pathway
    TGFB1 and acts as a mediator of TGFB1 induced matrix production in osteoblasts
    inhibited by statins (simvastatin) in mesangial cells
    KLF15 (KLF15 inhibits connective tissue growth factor (CTGF) expression in cardiac fibroblasts)
    repressed by NEUROG3
    Other is negatively regulated during neuron-glioblastoma interaction
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --over  
    in senescent prostatic epithelial cells and in fibrotic renal glomeruli
    constitutional       gain of function
    increased basal promoter activity in scleroderma fibroblasts
    constitutional     --over  
    in isolated cardiomyocytes, overexpression of CTGF induced hypertrophic growth
    constitutional     --over  
    in osteoarthritis (OA), highly expressed in OA synovial fibroblasts
    Susceptibility
  • to systemic sclerosis
  • to nephropathy in type 1 diabetes
    • Variant & Polymorphism other -945G allele is significantly associated with susceptibility to systemic sclerosis
  • variants within the promoter region predisposes diabetic subjects to develop albuminuria and Samd1 controls the expression of CTGF promoter through this region
    • Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS
  • Ccn2 null mutant mice
  • chondrocytes isolated from Ccn2-/- mice exhibit impaired type II collagen, aggrecan expression, and ECM synthesis