Connective-tissue growth factor (CTGF) modulates cell signalling by BMP and TGF-β

Abreu, José G.; Ketpura, Nan I.; Reversade, Bruno; Robertis, E. M. De

doi:10.1038/ncb826

Cited by 830 publications

(824 citation statements)

References 28 publications

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“…First, Cyr61 may bind directly to mesangial cells and exert its action, presumably through cell surface integrin complexes (see above). Second, Cyr61 might interact with PDGF in the media to interfere with its action, as is the case with CTGF and bone morphogenic protein 4 reported in Xenopus (33). Third, Cyr61 may alter secretion of other soluble factors such as extracellular matrix proteins (see below) from COS-7 cells, which have activity to modify mesangial cell migration.…”

Section: Discussionmentioning

confidence: 99%

Angiogenic Protein Cyr61 is Expressed by Podocytes in Anti-Thy-1 Glomerulonephritis

Sawai¹,

Mori²,

Mukoyama³

et al. 2003

Journal of the American Society of Nephrology

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Abstract. Dynamic recovery of glomerular structure occurs after severe glomerular damage in anti-Thy-1 glomerulonephritis (Thy-1 GN), but its mechanism remains to be investigated. To identify candidate genes possibly involved in glomerular reconstruction, screening was performed for genes that are specifically expressed by podocytes and are upregulated in glomeruli of Thy-1 GN. Among them, cysteine-rich protein 61 (Cyr61 or CCN1), a soluble angiogenic protein belonging to the CCN family, was identified. By Northern blot analysis, Cyr61 mRNA was markedly upregulated in glomeruli of Thy-1 GN from day 3 through day 7, when mesangial cell migration was most prominent. By in situ hybridization and immunohistochemistry, Cyr61 mRNA and protein were expressed by proximal straight tubules and afferent and efferent arterioles in normal rat kidneys and were intensely upregulated at podocytes in Thy-1 GN. Platelet-derived growth factor-BB (PDGF-BB) and transforming growth factor-␤1 (TGF-␤1), of which the gene expression in the glomeruli of Thy-1 GN was upregulated in similar time course as Cyr61, induced Cyr61 mRNA expression in cultured podocytes. Furthermore, supernatant of Cyr61-overexpressing cells inhibited PDGF-induced mesangial cell migration. In conclusion, it is shown that Cyr61 is strongly upregulated at podocytes in Thy-1 GN possibly by PDGF and TGF-␤. Cyr61 may be involved in glomerular remodeling as a factor secreted from podocytes to inhibit mesangial cell migration.

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Section: Discussionmentioning

confidence: 99%

Angiogenic Protein Cyr61 is Expressed by Podocytes in Anti-Thy-1 Glomerulonephritis

Sawai¹,

Mori²,

Mukoyama³

et al. 2003

Journal of the American Society of Nephrology

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“…No TGF-b isoforms were found to be increased in SSC; yet, CTGF is known to potentiate interactions between low levels of TGF-b1 and its cognate receptor. 29 Hence, we considered the possibility of TGF-b1-dependent signaling in this fibrogenic loop, even in the absence of elevated amounts of TGF-b1. Surprisingly, blockade of TGF-b signaling with a pan-TGF-b-neutralizing antibody did not prevent myofibroblast differentiation induced by either SSC or recombinant CTGF.…”

Section: Discussionmentioning

confidence: 99%

Caspase-3-mediated secretion of connective tissue growth factor by apoptotic endothelial cells promotes fibrosis

et al. 2009

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Apoptosis of endothelial cells (ECs) is an early pathogenic event in various fibrotic diseases. In this study, we evaluated whether paracrine mediators produced by apoptotic ECs play direct roles in fibrogenesis. C3H mice injected subcutaneously with serumfree medium conditioned by apoptotic ECs (SSC) showed increased skin thickness and heightened protein levels of a-smoothmuscle actin (aSMA), vimentin and collagen I as compared with mice injected with medium conditioned by non-apoptotic ECs. Fibroblasts exposed to SSC in vitro showed cardinal features of myofibroblast differentiation with increased stress fiber formation and expression of aSMA. Caspase-3 silencing in ECs prevented the release of mediators favoring myofibroblast differentiation. To identify the fibrogenic factor(s) released by ECs, the protein contents of media conditioned by either apoptotic or non-apoptotic ECs were compared using SDS-PAGE-liquid chromatography (LC)-tandem mass spectrometry (MS/MS) and two-dimensional LC-MS/MS. Connective tissue growth factor (CTGF) was the only fibrogenic protein found increased in SSC. Pan-caspase inhibition with ZVAD-FMK or caspase-3 silencing in ECs confirmed that CTGF was released downstream of caspase-3 activation. The fibrogenic signaling signatures of SSC and CTGF on fibroblasts in vitro were similarly Pyk2-, Src-family kinases-and PI3K dependent, but TGF-b-independent. CTGF-immunodepleted SSC failed to induce myofibroblast differentiation in vitro and skin fibrosis in vivo. These results identify caspase-3 activation in ECs as a novel inducer of CTGF release and fibrogenesis.

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“…While Chordin blocks BMP/receptor interactions, the CR domain protein KCP enhances BMP/receptor interactions to in-crease the efficacy of signaling (11). Similarly, the CR domain protein connective tissue growth factor (CTGF) also enhances TGF-␤-mediated signaling while suppressing the BMP-dependent pathway (1).…”

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confidence: 99%

The Cysteine-Rich Domain Protein KCP Is a Suppressor of Transforming Growth Factor β/Activin Signaling in Renal Epithelia

Lin¹,

Patel

Wang³

et al. 2006

Molecular and Cellular Biology

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The transforming growth factor ␤ (TGF-␤) superfamily, including the bone morphogenetic protein (BMP) and TGF-␤/activin A subfamilies, is regulated by secreted proteins able to sequester or present ligands to receptors. KCP is a secreted, cysteine-rich (CR) protein with similarity to mouse Chordin and Xenopus laevis Kielin. KCP is an enhancer of BMP signaling in vertebrates and interacts with BMPs and the BMP type I receptor to promote receptor-ligand interactions. Mice homozygous for a KCP null allele are hypersensitive to developing renal interstitial fibrosis, a disease stimulated by TGF-␤ but inhibited by BMP7. In this report, the effects of KCP on TGF-␤/activin A signaling are examined. In contrast to the enhancing effect on BMPs, KCP inhibits both activin A-and TGF-␤1-mediated signaling through the Smad2/3 pathway. These inhibitory effects of KCP are mediated in a paracrine manner, suggesting that direct binding of KCP to TGF-␤1 or activin A can block the interactions with prospective receptors. Consistent with this inhibitory effect, primary renal epithelial cells from KCP mutant cells are hypersensitive to TGF-␤ and exhibit increased apoptosis, dissociation of cadherin-based cell junctions, and expression of smooth muscle actin. Furthermore, KCP null animals show elevated levels of phosphorylated Smad2 after renal injury. The ability to enhance BMP signaling while suppressing TGF-␤ activation indicates a critical role for KCP in modulating the responses between these antiand profibrotic cytokines in the initiation and progression of renal interstitial fibrosis.The transforming growth factor ␤ (TGF-␤) superfamily encodes growth and differentiation factors that regulate a wide variety of cellular processes. The members of the TGF-␤ superfamily include two major branches, bone morphogenetic proteins (BMPs) and TGF-␤s/activins (19). TGF-␤ signaling is initiated by the binding of the ligand to a specific pair of type I and type II transmembrane receptors, leading to the phosphorylation of the cytoplasmic serine/threonine kinase domains (19,25). The type I receptors, also known as activinlinked kinases (ALKs), then transduce signals downstream by phosphorylation of receptor-activated Smad proteins. The Smad family can be divided into three distinct subfamilies: receptor-activated Smads (R-Smad), common-partner Smads (Co-Smad), and inhibitory Smads. Whereas Smad1, Smad5, and Smad8 are phosphorylated by BMP type I receptors (ALK-2, ALK-3, and ALK-6), Smad2 and Smad3 are activated by TGF-␤ and activin type I receptors (ALK-5 and ALK-4). The R-Smad and the Co-Smad (Smad4) form a heterooligomer which translocates into the nucleus and regulates expression of ligand-responsive genes. Inhibitory Smads include Smad6 and Smad7, which prevent the activation of R-and Co-Smad.While members of the TGF-␤ superfamily use similar mechanisms to signal to the nucleus, the two major branches achieve specificity by using different elements. Outside the cell, each ligand of the TGF-␤ superfamily binds to specific pairs of the recept...

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Connective-tissue growth factor (CTGF) modulates cell signalling by BMP and TGF-β

Cited by 830 publications

References 28 publications

Angiogenic Protein Cyr61 is Expressed by Podocytes in Anti-Thy-1 Glomerulonephritis

Angiogenic Protein Cyr61 is Expressed by Podocytes in Anti-Thy-1 Glomerulonephritis

Caspase-3-mediated secretion of connective tissue growth factor by apoptotic endothelial cells promotes fibrosis

The Cysteine-Rich Domain Protein KCP Is a Suppressor of Transforming Growth Factor β/Activin Signaling in Renal Epithelia

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