CCN2 (connective tissue growth factor) promotes fibroblast adhesion to fibronectin.
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 alpha4 beta1 and alpha5 and syndecan 4. Using Ccn2-/- mouse embryonic fibroblasts, we show that loss of endogenous CCN2 results in impaired spreading on fibronectin, delayed alpha-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.
Chen
Yunliang
Y
Centre for Rheumatology, Royal Free and University College Medical School, University College London (Royal Free Campus), Hampstead, London NW3 2PF, United Kingdom.
Abraham
David J
DJ
Shi-Wen
Xu
X
Pearson
Jeremy D
JD
Black
Carol M
CM
Lyons
Karen M
KM
Leask
Andrew
A
D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism*; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D022001:Focal Adhesions / Q000502:physiology; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011509:Proteoglycans / Q000378:metabolism; D011554:Pseudopodia / Q000502:physiology; D012867:Skin / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D053667:Syndecans
D002070:Butadienes; C526317:CCN2 protein, human; C526318:CCN2 protein, mouse; D005353:Fibronectins; D017874:Immediate-Early Proteins; D016023:Integrins; D036341:Intercellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D009570:Nitriles; D011509:Proteoglycans; D053667:Syndecans; C113580:U 0126; D055513:Connective Tissue Growth Factor; D006493:Heparin; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; C496051:Ptk2 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases