ArticlePloS one2011
CCN2 is required for the TGF-β induced activation of Smad1-Erk1/2 signaling network.
Article in PloS one, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 84 citations in OpenAlex.
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- Protein-Bound Uremic Toxins in Senescence and Kidney Fibrosis.Biomedicines · 2023Review
- Comparative proteomics reveals elevated CCN2 in NGLY1-deficient cells.Biochemical and biophysical research communications · 2022Article
- Scalable Generation of Nanovesicles from Human-Induced Pluripotent Stem Cells for Cardiac Repair.International journal of molecular sciences · 2022Article
- Remodeling of the Lamina Cribrosa: Mechanisms and Potential Therapeutic Approaches for Glaucoma.International journal of molecular sciences · 2022Review
- Ccn2a is an injury-induced matricellular factor that promotes cardiac regeneration in zebrafish.Development (Cambridge, England) · 2021Article
- Blocking CCN2 preferentially inhibits osteoclastogenesis induced by repetitive high force bone loading.Connective tissue research · 2021Article
- Transcriptional Profiling of Porcine HCC Xenografts Provides Insights Into Tumor Cell Microenvironment Signaling.Frontiers in genetics · 2021Article
- Pro-Fibrotic Phenotype in a Patient with Segmental Stiff Skin Syndrome via TGF-β Signaling Overactivation.International journal of molecular sciences · 2020Article
- The effects of inhibiting the activation of hepatic stellate cells by lignan components from the fruits of Schisandra chinensis and the mechanism of schisanhenol.Journal of natural medicines · 2020Article
- Connective Tissue Growth Factor Inhibition Enhances Cardiac Repair and Limits Fibrosis After Myocardial Infarction.JACC. Basic to translational science · 2019Article
- Onset and Progression of Human Osteoarthritis-Can Growth Factors, Inflammatory Cytokines, or Differential miRNA Expression Concomitantly Induce Proliferation, ECM Degradation, and Inflammation in Articular Cartilage?International journal of molecular sciences · 2018Review
- Multifaced Roles of the αvβ3 Integrin in Ehlers-Danlos and Arterial Tortuosity Syndromes' Dermal Fibroblasts.International journal of molecular sciences · 2018Review
- Scar management in burn injuries using drug delivery and molecular signaling: Current treatments and future directions.Advanced drug delivery reviews · 2018Review
- The Activation of Human Dermal Microvascular Cells by Poly(I:C), Lipopolysaccharide, Imiquimod, and ODN2395 Is Mediated by the Fli1/FOXO3A Pathway.Journal of immunology (Baltimore, Md. : 1950) · 2018Article
- Adiponectin Is Involved in Connective Tissue Growth Factor-Induced Proliferation, Migration and Overproduction of the Extracellular Matrix in Keloid Fibroblasts.International journal of molecular sciences · 2017Article
- ERK1/2 directly acts on CTGF/CCN2 expression to mediate myocardial fibrosis in cardiomyopathy caused by mutations in the lamin A/C gene.Human molecular genetics · 2016Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Connective tissue growth factor (CCN2) is a multifunctional matricellular protein, which is frequently overexpressed during organ fibrosis. CCN2 is a mediator of the pro-fibrotic effects of TGF-β in cultured cells, but the specific function of CCN2 in the fibrotic process has not been elucidated. In this study we characterized the CCN2-dependent signaling pathways that are required for the TGF-β induced fibrogenic response. By depleting endogenous CCN2 we show that CCN2 is indispensable for the TGF-β-induced phosphorylation of Smad1 and Erk1/2, but it is unnecessary for the activation of Smad3. TGF-β stimulation triggered formation of the CCN2/β(3) integrin protein complexes and activation of Src signaling. Furthermore, we demonstrated that signaling through the α(v)β(3) integrin receptor and Src was required for the TGF-β induced Smad1 phosphorylation. Recombinant CCN2 activated Src and Erk1/2 signaling, and induced phosphorylation of Fli1, but was unable to stimulate Smad1 or Smad3 phosphorylation. Additional experiments were performed to investigate the role of CCN2 in collagen production. Consistent with the previous studies, blockade of CCN2 abrogated TGF-β-induced collagen mRNA and protein levels. Recombinant CCN2 potently stimulated collagen mRNA levels and upregulated activity of the COL1A2 promoter, however CCN2 was a weak inducer of collagen protein levels. CCN2 stimulation of collagen was dose-dependent with the lower doses (<50 ng/ml) having a stimulatory effect and higher doses having an inhibitory effect on collagen gene expression. In conclusion, our study defines a novel CCN2/α(v)β(3) integrin/Src/Smad1 axis that contributes to the pro-fibrotic TGF-β signaling and suggests that blockade of this pathway may be beneficial for the treatment of fibrosis.
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