Integrin-dependent functions of the angiogenic inducer NOV (CCN3): implication in wound healing.
The novel angiogenic inducer CCN3 (NOV, nephroblastoma overexpressed) is a matricellular protein of the CCN family, which also includes CCN1 (CYR61), CCN2 (CTGF), CCN4 (WISP-1), CCN5 (WISP-2), and CCN6 (WISP-3). CCN3 is broadly expressed in derivatives of all three germ layers during mammalian development, and its deranged expression is associated with vascular injury and a broad range of tumors. We have shown that CCN3 promotes proangiogenic activities in vascular endothelial cells through integrin receptors and induces neovascularization in vivo (Lin, C. G., Leu, S. J., Chen, N., Tebeau, C. M., Lin, S. X., Yeung, C. Y., and Lau, L. F. (2003) J. Biol. Chem. 278, 24200-24208). In this study, we show that CCN3 is highly expressed in granulation tissue of cutaneous wounds 5-7 days after injury and is capable of inducing responses in primary fibroblasts consistent with wound healing. Purified CCN3 supports primary skin fibroblast adhesion through integrins alpha(5)beta(1) and alpha(6)beta(1) and induces fibroblast chemotaxis through integrin alpha(v)beta(5). We show that CCN3 is a novel ligand of alpha(v)beta(5) in a solid phase binding assay. Although not mitogenic on its own, CCN3 also enhances basic fibroblast growth factor-induced DNA synthesis. Furthermore, CCN3 up-regulates MMP-1 and PAI-1 expression but interacts with TGF-beta1 in an antagonistic or synergistic manner to regulate the expression of specific genes. These findings, together with its angiogenic activity, support a role for CCN3 in cutaneous wound healing in skin fibroblasts and establish its matricellular mode of action through integrin receptors.
Lin
Cristiane G
CG
Department of Biochemistry and Molecular Genetics, University of Illinois College of Medicine, Chicago, Illinois 60607-7170, USA.
Chen
Chih-Chiun
CC
Leu
Shr-Jeng
SJ
Grzeszkiewicz
Tatiana M
TM
Lau
Lester F
LF
D002448:Cell Adhesion; D002465:Cell Movement; D002633:Chemotaxis; D055513:Connective Tissue Growth Factor; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism / Q000502:physiology*; D007150:Immunohistochemistry; D039081:Integrin alpha5beta1 / Q000378:metabolism; D039121:Integrin alpha6beta1 / Q000378:metabolism; D016023:Integrins / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism / Q000502:physiology*; D008024:Ligands; D018919:Neovascularization, Physiologic; D055514:Nephroblastoma Overexpressed Protein; D011485:Protein Binding; D012313:RNA / Q000737:chemistry; D019030:Receptors, Vitronectin / Q000378:metabolism; D012867:Skin / Q000378:metabolism; D013936:Thymidine / Q000737:chemistry; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D015854:Up-Regulation; D014945:Wound Healing
C526317:CCN2 protein, human; C526319:CCN3 protein, human; D017874:Immediate-Early Proteins; D039081:Integrin alpha5beta1; D039121:Integrin alpha6beta1; D016023:Integrins; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D055514:Nephroblastoma Overexpressed Protein; D019030:Receptors, Vitronectin; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C064660:integrin alphaVbeta5; D016222:Fibroblast Growth Factor 2; D055513:Connective Tissue Growth Factor; D012313:RNA; D004247:DNA; D013936:Thymidine