The CCN family of angiogenic regulators: the integrin connection

LF Lau, SCT Lam - Experimental cell research, 1999 - Elsevier
LF Lau, SCT Lam
Experimental cell research, 1999Elsevier
The recent discovery of two structurally related angiogenic inducers, CYR61 and
FISP12/CTGF, has brought to light an emerging family of conserved and modular proteins
with protean functions (Babic et al., 1998, 1999). This protein family now consists of six
distinct members (Fig. 1), including CYR61 (cysteinerich), CTGF (connective tissue growth
factor), NOV (nephroblastoma overexpressed), ELM-1 (expressed in low-metastatic cells),
WISP-3 (Wnt-1-induced secreted protein), and COP-1 (whose regulation is opposite of MOB …
The recent discovery of two structurally related angiogenic inducers, CYR61 and FISP12/CTGF, has brought to light an emerging family of conserved and modular proteins with protean functions (Babic et al., 1998, 1999). This protein family now consists of six distinct members (Fig. 1), including CYR61 (cysteinerich), CTGF (connective tissue growth factor), NOV (nephroblastoma overexpressed), ELM-1 (expressed in low-metastatic cells), WISP-3 (Wnt-1-induced secreted protein), and COP-1 (whose regulation is opposite of MOB-1). CYR61, CTGF, and NOV were among the first of this group to be identified, leading to the referral of this family of proteins as the “CCN family”(Bork, 1993). Orthologs of this family have been found across vertebrate species from Xenopus to human. Although characterization of the CCN family began a decade ago via cDNA cloning, these proteins have not received broad attention heretofore and interest in them has only recently begun to escalate. This is partly due to the fact that members of the family exhibit such diversity of functions that their activities and modes of actions have defied simple classification. Where examined, CCN proteins are secreted, extracellular matrix (ECM)-associated proteins that regulate such cellular processes as adhesion, migration, mitogenesis, differentiation, and survival. They also regulate more complex biological processes such as angiogenesis and chondrogenesis and have been implicated in wound healing, tumorigenesis, and fibrotic and vascular diseases. In this review, we endeavor to provide a mechanistic interpretation of these diverse functions based on the recent discovery that CYR61 and CTGF are novel ligands of integrins (Kireeva et al., 1998; Babic et al., 1999; Jedsadayanmata et al., 1999). Signaling through integrin receptors may explain many, if not all, of the known activities of CCN proteins. To date, there have been no other types of signaling receptors identified for CCN proteins; however, their existence cannot be ruled out. Here we have emphasized the functional significance of the CCN family and their mechanisms of actions through integrin receptors, rather than to present a comprehensive summary of work done on members of this family. Other perspectives on this family of proteins have emphasized their possible involvement in wound healing, fibrosis, and atherosclerosis (Igarashi et al., 1992; Grotendorst, 1997; Oemar and Luscher, 1997).
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