All in the CCN family: essential matricellular signaling modulators emerge from the bunker

Andrew Leask, David J. Abraham

The CCN family is a group of six secreted proteins that specifically associate with the extracellular matrix. Structurally, CCN proteins are modular, containing up to four distinct functional domains. CCN family members are induced by growth factors and cytokines such as TGFbeta and endothelin 1 and cellular stress such as hypoxia, and are overexpressed in pathological conditions that affect connective tissues, including scarring, fibrosis and cancer. Although CCN family members were discovered over a decade ago, the precise biological role, mechanism of action and physiological function of these proteins has remained elusive until recently, when several key mechanistic insights into the CCN family emerged. The CCNs have been shown to have key roles as matricellular proteins, serving as adaptor molecules connecting the cell surface and extracellular matrix (ECM). Although they appear not to have specific high-affinity receptors, they signal through integrins and proteoglycans. Furthermore, in addition to having inherent adhesive abilities that modulate focal adhesions and control cell attachment and migration, they execute their functions by modulating the activity of a variety of different growth factors, such as TGFbeta. CCN proteins not only regulate crucial biological processes including cell differentiation, proliferation, adhesion, migration, apoptosis, ECM production, chondrogenesis and angiogenesis, but also have more sinister roles promoting conditions such as fibrogenesis.