Nomenclature of the CCN family of genes is based on cysteine-rich protein 61 (Cyr61; CCN1), connective tissue growth factor (CTGF;CCN2) and nephroblastoma overexpressed protein (Nov; CCN3). The CCN family currently comprises six secreted proteins with a similar modular secondary structure (Fig. from Perbal and Perbal 2007
; Fig. and from Leask and Abraham 2006
; Fig. from Kubota and Takigawa 2007
). CCN proteins comprise four domains: an insulin-like growth factor binding protein (IGFBP) domain (domain I), a Von Willebrand factor domain (domain II), a thrombospondin-homology domain (domain III), and a cysteine knot, heparin-binding domain (domain IV). An N-terminal located signal sequence and a hinge region between domains II and III govern secretion and susceptibility to proteinase cleavage, respectively. Cleaved fragments may possess unique biological functions, yet to be determined.
Fig. 1 Schematic representation of the multiple types of interactions in which CCN proteins may be involved for signaling cell functions. CCN CCN proteins, L ligands of receptors, R receptor. ECM extracellular matrix, P potential partners in the extracellular (more ...)
Fig. 2 Signaling by CCN family members, CCN1, CCN2 and CCN3 bind TGFβ, fibronectin, integrins, LRP1 and HSPGs as indicated. CCN proteins appear to signal principally through the C-terminal quarter (domain IV) to activate adhesive signaling pathways and (more ...)
Fig. 3 Regualation of the CCN2 promoter and 3′ untranslated region (3′ UTR). The CCN2 promoter contains recognition sequences for HIF, Smad, BCE-1, Ets-1, Sp1, as indicated. The 3′ UTR of the gene (white rectangle) contains a cis-acting (more ...)
Fig. 4 A The primary structure of the CCN family proteins and their reported variants. The general structure is composed of four conserved modules is illustrated as a nascent translation product with a signal peptide for secretion (S) at the top. The module (more ...)
Since their first discovery 15 years ago much has been learned about the biochemistry of CCN proteins and their expression during development, in normal adult tissues and in disease. In vitro studies and more recently CCN transgenic and knockout mice have yielded further insights and a better understanding of the diversity and complexity of CCN activities. It is now well accepted that CCN proteins are not growth factors but matricellular proteins that modify signaling of other molecules, in particular those associated with the extracellular matrix. CCN proteins are involved in mitosis, adhesion, apoptosis, extracellular matrix production, growth arrest and migration of multiple cell types. In fact they are expressed early in development and then are differentially recruited by cells to facilitate multiple tissue/organ functions, and critically during wound healing and disease. The field is comprehensively covered in a recent monograph by Perbal and Takigawa (2005
The current state of knowledge on the CCN proteins and interacting protein partners suggest that the CCN proteins integrate communication between the extracellular matrix and the cell surface (Fig ; Perbal and Perbal 2007
). As depicted in Fig. from Leask & Abrahams review (2006
) domains III and IV bind integrins, LRP1 receptor and HSPG to effect intracellular signaling of key pathways. CCN proteins mitigate activities of the ECM and associated growth factors like TGFβ, BMP4, IGFs, and VEGF. This positions the CCN proteins in the matricellular sphere and as controllers of cell–matrix communications.
Interestingly, truncated forms of the CCN proteins appear to translocate to the nucleus where they are postulated to be involved in transcriptional regulation. Theoretically, this may serve as the means to transmit environmental information to central control. In support of this notion that CCN genes are sensitive to environmental conditions, Fig. from Leask and Abrahams review (2006
) shows how CCN2 can be regulated by hypoxia and injury/inflammatory mediators.
Figures and from Kubota and Takigawa review (2007
) depicts how CCN proteins figure prominently in angiogenesis during normal development of tissues and organs and during tumor angiogenesis. CCN2 is a well established promoter and inducer of the chondrogenic and osteogenic lineages placing it in the centre of skeletal formation and deformation.
Fig. 5 A The general mechanism of angiogenic action of the CCN proteins. Through the interaction with integrins, angiogenic CCN proteins, such as CCN1, CCN2 and CCN3, promote the migration, adhesion and survival of vascular endothelial cells. CCN proteins are (more ...)
Fig. 6 Assignment of the functioning stages for angiogenic CCN proteins in the angiogenic events throughout the life. According to the accumulating findings, CCN1 appears to play a critical role in the earlier stages of embryonic vascular development, while (more ...)
Looking at the structural similarities amongst the CCN proteins it was at first not easily understandable what functional differences could exist. It now turns out that the CCN proteins likely comprise a homeostatic regulatory system where one member drives a process while a closely related member can inhibit the same process. Although the molecular details of this regulation are not yet well understood the concept has stirred great interest given that it may open up new means for therapeutic manipulation of disease processes. Thus in this battle between the CCN family members the relative expression levels of individual CCN proteins, full length and shorter versions, (often multiple in one site) may ultimately decide the character of physiological and pathological processes. Figure from Chaqour and Goppelt-Struebe review (2006
) illustrates another key component in the biology of CCN proteins, that is, modulation by dynamic forces that act upon cells. In pathological conditions like hypertension, obstruction and hemodynamic overload, altered signaling induced by stretching and compression forces on cells modulates CCN expression and can lead to either positive compensatory responses or to aberrant outcomes such as fibrosis. Thus CCN2 has attracted considerable attention as a fibrosis inducing CCN protein when overexpressed or when prolonged in its activity. Recent studies have demonstrated how downregulating CCN2 expression and function ameliorates the pathological process. Importantly, due to their secretory status, CCN proteins are also biomarkers of the pathological process.
Fig. 7 Schematic model of the mechanical regulation of Cyr61 and CTGF indicating different regulatory levels and open questions (see Conclusion). Mediators, which have been related to mechanical stimulation of Cr61 or CTGF gene induction, are shown in the middle (more ...)