scholarly journals CCN2 (Connective Tissue Growth Factor) Promotes Fibroblast Adhesion to Fibronectin

2004 ◽  
Vol 15 (12) ◽  
pp. 5635-5646 ◽  
Author(s):  
Yunliang Chen ◽  
David J. Abraham ◽  
Xu Shi-wen ◽  
Jeremy D. Pearson ◽  
Carol M. Black ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Growth Factor ◽  
Protein Kinase ◽  
Connective Tissue ◽  
Connective Tissue Growth Factor ◽  
Tissue Growth ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
Fibroblast Adhesion

In vivo, CCN2 (connective tissue growth factor) promotes angiogenesis, osteogenesis, tissue repair, and fibrosis, through largely unknown mechanisms. In vitro, CCN2 promotes cell adhesion in a variety of systems via integrins and heparin sulfate proteoglycans (HSPGs). However, the physiological relevance of CCN2-mediated cell adhesion is unknown. Here, we find that HSPGs and the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase cascade are required for adult human dermal fibroblasts to adhere to CCN2. Endogenous CCN2 directly binds fibronectin and the fibronectin receptors integrins α4 β1 and α5 and syndecan 4. Using Ccn2-/- mouse embryonic fibroblasts, we show that loss of endogenous CCN2 results in impaired spreading on fibronectin, delayed α-smooth muscle actin stress fiber formation, and reduced ERK and focal adhesion kinase phosphorylation. These results suggest that a physiological role of CCN2 is to potentiate the ability of fibroblasts to spread on fibronectin, which may be important in modulating fibroblast adhesion to the provisional matrix during tissue development and wound healing. These results are consistent with the notion that a principal function of CCN2 is to modulate receptor/ligand interactions in vivo.

scholarly journals Connective tissue growth factor (CTGF) promotes activated mesangial cell survival via up-regulation of mitogen-activated protein kinase phosphatase-1 (MKP-1)

2007 ◽  
Vol 406 (1) ◽  
pp. 131-138 ◽  
Author(s):  
Nadia Wahab ◽  
Dimity Cox ◽  
Abigail Witherden ◽  
Roger M. Mason
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Protein Kinase ◽  
Connective Tissue ◽  
P38 Mapk ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Tissue Growth ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein

Activated mesangial cells are thought to play a pivotal role in the development of kidney fibrosis under chronic pathological conditions, including DN (diabetic nephropathy). Their prolonged survival may enhance the development of the disease since they express increased amounts of growth factors and extracellular matrix proteins. CTGF (connective tissue growth factor) is one of the growth factors produced by activated mesangial cells and is reported to play a key role in the pathogenesis of DN. Previous studies have shown that addition of exogenous CTGF to HMCs (human mesangial cells) rapidly activates ERK1/2 (extracellular-signal-regulated kinase 1/2) MAPK (mitogen-activated protein kinase) and JNK (c-Jun N-terminal kinase) MAPK, but not the p38 MAPK, despite the activation of the upstream kinases, MKK3/6 (MAPK kinase 3/6). The aim of the present study was to investigate whether the lack of phosphorylated p38 MAPK by CTGF has an anti-apoptotic effect on activated HMCs. We show that in HMC CTGF induces the rapid transcriptional activation and synthesis of MKP-1 (MAPK phosphatase-1), a dual specificity phosphatase that dephosphorylates p38 MAPK. This in turn prevents the anti-apoptotic protein, Bcl-2, from being phosphorylated and losing its function, leading to the survival of the cells. Knockout of MKP-1 protein in mesangial cells treated with CTGF, using siRNA (small interfering RNA) or antisense oligonucleotides, allows p38 MAPK activation and induces mesangial cell death.

scholarly journals Effect of Connective Tissue Growth Factor on Protein Kinase Expression and Activity in Human Corneal Fibroblasts

2012 ◽  
Vol 53 (13) ◽  
pp. 8076 ◽  
Author(s):  
Siva S. Radhakrishnan ◽  
Timothy D. Blalock ◽  
Paulette M. Robinson ◽  
Genevieve Secker ◽  
Julie Daniels ◽  
...  
Keyword(s):  
Growth Factor ◽  
Protein Kinase ◽  
Connective Tissue ◽  
Connective Tissue Growth Factor ◽  
Tissue Growth ◽  
Corneal Fibroblasts ◽  
Kinase Expression ◽  
Expression And Activity

scholarly journals Expression of Connective Tissue Growth Factor in Human Renal Fibroblasts: Regulatory Roles of RhoA and cAMP

2001 ◽  
Vol 12 (9) ◽  
pp. 1853-1861 ◽  
Author(s):  
JULIANE HEUSINGER-RIBEIRO ◽  
MICHAEL EBERLEIN ◽  
NADIA ABDEL WAHAB ◽  
MARGARETE GOPPELT-STRUEBE
Keyword(s):  
Growth Factor ◽  
Protein Kinase ◽  
Connective Tissue ◽  
Protein Kinase A ◽  
Connective Tissue Growth Factor ◽  
Tissue Growth ◽  
Cytochalasin D ◽  
Small Gtpase ◽  
General Role ◽  
Kinase A

Abstract. The induction of connective tissue growth factor (CTGF) was investigated in a human renal fibroblast cell line that exhibited many characteristics of primary human renal fibroblasts. Induction of CTGF mRNA was observed after treatment of the cells with transforming growth factor-β (TGF-β) or, even more prominently, lysophosphatidic acid (LPA). LPA induced a rapid transient increase in CTGF mRNA expression, with maximal levels being observed after 1 to 2 h. This increase was accompanied by CTGF protein synthesis. Induction of CTGF was insensitive to pertussis toxin and was not dependent on the activation of p42/44 mitogen-activated protein kinases. Inhibition of the proteins of the Rho family with toxin B from Clostridium difficile abrogated basal and LPA-mediated induction of CTGF. Specific targeting of RhoA with C3 exotoxin or of the Rho kinases with the inhibitor Y-27632 similarly prevented induction of CTGF, implicating RhoA as a signaling module downstream of LPA. Inhibition of RhoA depolymerized the actin cytoskeleton, as did treatment with cytochalasin D. Preincubation of the human renal fibroblasts with cytochalasin D prevented induction of CTGF by LPA, indicating a strong contribution of an intact cytoskeleton. Interference with RhoA signaling similarly inhibited the induction of CTGF by TGF-β. Elevation of intracellular levels of cAMP and thus activation of protein kinase A prevented induction of CTGF expression. The cytoskeletal effects of cAMP, however, were reversed by LPA. These data indicate complex interactions involving LPA-mediated activation of RhoA- and protein kinase A-dependent signaling pathways. The data thus demonstrate the regulatory functions of the small GTPase RhoA and of an intact cytoskeleton in the expression of CTGF after stimulation with LPA or TGF-β. Analogous signal transduction pathways were previously demonstrated in rat mesangial cells, suggesting a more general role for RhoA in the regulation of CTGF expression.

scholarly journals Fisp12/Mouse Connective Tissue Growth Factor Mediates Endothelial Cell Adhesion and Migration through Integrin αvβ3, Promotes Endothelial Cell Survival, and Induces Angiogenesis In Vivo

1999 ◽  
Vol 19 (4) ◽  
pp. 2958-2966 ◽  
Author(s):  
Alexander M. Babic ◽  
Chih-Chiun Chen ◽  
Lester F. Lau
Keyword(s):  
Endothelial Cells ◽  
Cell Adhesion ◽  
Endothelial Cell ◽  
Growth Factor ◽  
Connective Tissue ◽  
Tissue Growth ◽  
Microvascular Endothelial Cells ◽  
Endothelial Cell Survival ◽  
Vessel Growth

ABSTRACT Fisp12 was first identified as a secreted protein encoded by a growth factor-inducible immediate-early gene in mouse fibroblasts, whereas its human ortholog, CTGF (connective tissue growth factor), was identified as a mitogenic activity in conditioned media of human umbilical vein endothelial cells. Fisp12/CTGF is a member of a family of secreted proteins that includes CYR61, Nov, Elm-1, Cop-1/WISP-2, and WISP-3. Fisp12/CTGF has been shown to promote cell adhesion and mitogenesis in both fibroblasts and endothelial cells and to stimulate cell migration in fibroblasts. These findings, together with the localization of Fisp12/CTGF in angiogenic tissues, as well as in atherosclerotic plaques, suggest a possible role for Fisp12/CTGF in the regulation of vessel growth during development, wound healing, and vascular disease. In this study, we show that purified Fisp12 (mCTGF) protein promotes the adhesion of microvascular endothelial cells through the integrin receptor αvβ3. Furthermore, Fisp12 stimulates the migration of microvascular endothelial cells in culture, also through an integrin-αvβ3-dependent mechanism. In addition, the presence of Fisp12 promotes endothelial cell survival when cells are plated on laminin and deprived of growth factors, a condition that otherwise induces apoptosis. In vivo, Fisp12 induces neovascularization in rat corneal micropocket implants. These results demonstrate that Fisp12 is a novel angiogenic inducer and suggest a direct role for Fisp12 in the adhesion, migration, and survival of endothelial cells during blood vessel growth. Taken together with the recent finding that the related protein CYR61 also induces angiogenesis, we suggest that Fisp12/mCTGF and CYR61 comprise prototypes of a new family of angiogenic regulators that function, at least in part, through integrin-αvβ3-dependent pathways.

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