ArticleThe Journal of biological chemistry2018
Connective tissue growth factor (CCN2) is a matricellular preproprotein controlled by proteolytic activation.
Article in The Journal of biological chemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Who cites it
47 citing papers in PubMed, 64 citations in OpenAlex.
- CCN Proteins as Matricellular Regulators of Bone in Aging and Disease.Current osteoporosis reports · 2025Review
- Matricellular proteins in immunometabolism and tissue homeostasis.BMB reports · 2024Review
- An overview of CCN4 (WISP1) role in human diseases.Journal of translational medicine · 2024Review
- Obstructive nephropathy and molecular pathophysiology of renal interstitial fibrosis.Physiological reviews · 2023Review
- Blocking CCN2 Reduces Established Bone Loss Induced by Prolonged Intense Loading by Increasing Osteoblast Activity in Rats.JBMR plus · 2023Article
- Structural insights into regulation of CCN protein activities and functions.Journal of cell communication and signaling · 2023Review
- Cooperation is the key: the CCN biological system as a gate to high complex protein superfamilies' signaling.Journal of cell communication and signaling · 2023Article
- Fibrosis: Types, Effects, Markers, Mechanisms for Disease Progression, and Its Relation with Oxidative Stress, Immunity, and Inflammation.International journal of molecular sciences · 2023Review
- Episodic Binge-like Ethanol Reduces Skeletal Muscle Strength Associated with Atrophy, Fibrosis, and Inflammation in Young Rats.International journal of molecular sciences · 2023Article
- The carboxyl-terminal TSP1-homology domain is the biologically active effector peptide of matricellular protein CCN5 that counteracts profibrotic CCN2.The Journal of biological chemistry · 2023Article
- Module 4-Deficient CCN2/Connective Tissue Growth Factor Attenuates the Progression of Renal Fibrosis via Suppression of Focal Adhesion Kinase Phosphorylation in Tubular Epithelial Cells.Molecular and cellular biology · 2023Article
- Analysis of the Function of CCN2 in Tubular Epithelium Cells with a Focus on Renal Fibrogenesis.Methods in molecular biology (Clifton, N.J.) · 2023Article
- Identification and Characterization of a Novel Nanobody Against Human CTGF to Reveal Its Antifibrotic Effect in an in vitro Model of Liver Fibrosis.International journal of nanomedicine · 2023Article
- Western Blot Protocols for Analysis of CCN Proteins and Fragments in Exosomes, Vesicle-Free Fractions, and Cells.Methods in molecular biology (Clifton, N.J.) · 2023Article
- The CCN2 Polymorphism rs12526196 Is a Risk Factor for Ascending Thoracic Aortic Aneurysm.International journal of molecular sciences · 2022Article
- Tissue distribution and transcriptional regulation of CCN5 in the heart after myocardial infarction.Journal of cell communication and signaling · 2022Article
- Fibroblast Growth Factors and Cellular Communication Network Factors: Intimate Interplay by the Founding Members in Cartilage.International journal of molecular sciences · 2022Review
- TAILS Identifies Candidate Substrates and Biomarkers of ADAMTS7, a Therapeutic Protease Target in Coronary Artery Disease.Molecular & cellular proteomics : MCP · 2022Article
- CCN2 Binds to Tubular Epithelial Cells in the Kidney.Biomolecules · 2022Article
- CCN2-induced lymphangiogenesis is mediated by the integrin αvβ5-ERK pathway and regulated by DUSP6.Scientific reports · 2022Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Connective tissue growth factor (CTGF; now often referred to as CCN2) is a secreted protein predominantly expressed during development, in various pathological conditions that involve enhanced fibrogenesis and tissue fibrosis, and in several cancers and is currently an emerging target in several early-phase clinical trials. Tissues containing high CCN2 activities often display smaller degradation products of full-length CCN2 (FL-CCN2). Interpretation of these observations is complicated by the fact that a uniform protein structure that defines biologically active CCN2 has not yet been resolved. Here, using DG44 CHO cells engineered to produce and secrete FL-CCN2 and cell signaling and cell physiological activity assays, we demonstrate that FL-CCN2 is itself an inactive precursor and that a proteolytic fragment comprising domains III (thrombospondin type 1 repeat) and IV (cystine knot) appears to convey all biologically relevant activities of CCN2. In congruence with these findings, purified FL-CCN2 could be cleaved and activated following incubation with matrix metalloproteinase activities. Furthermore, the C-terminal fragment of CCN2 (domains III and IV) also formed homodimers that were ∼20-fold more potent than the monomeric form in activating intracellular phosphokinase cascades. The homodimer elicited activation of fibroblast migration, stimulated assembly of focal adhesion complexes, enhanced RANKL-induced osteoclast differentiation of RAW264.7 cells, and promoted mammosphere formation of MCF-7 mammary cancer cells. In conclusion, CCN2 is synthesized and secreted as a preproprotein that is autoinhibited by its two N-terminal domains and requires proteolytic processing and homodimerization to become fully biologically active.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.