Conjunction junction, what's the function? CCN proteins as targets in fibrosis and cancers

Abstract

Cellular communication network (CCN) proteins are matricellular proteins that coordinate signaling among extracellular matrix, secreted proteins, and cell surface receptors. Their specific in vivo function is context-dependent, but they play profound roles in pathological conditions, such as fibrosis and cancers. Anti-CCN therapies are in clinical consideration. Only recently, however, has the function of these complex molecules begun to emerge. This review summarizes and interprets our current knowledge regarding these fascinating molecules and provides experimental evidence for their utility as therapeutic targets.

Keywords: CCN proteins; cancer; fibrosis; matricellular proteins; microenvironment.

Fig. 1.

Combinatorial interactions dictate cellular communication network (CCN) function. Each domain of CCN proteins interacts with different ligands. What CCN domains are present in the microenvironment depends on which CCN molecules are being synthesized [for example, CCN5 lacks the heparin-binding carboxy-terminal (CT) domain], protease activity, and differential splicing. The affinity of CCN molecules for each ligand is likely to vary. Thus, the overall biological effect of CCN proteins can vary widely depending on bioavailability of CCN proteins, their modules/fragments, and their interacting partners. CCN proteins act as central mediators of mechanotransduction. BMP, bone morphogenetic protein; HSPG, heparan sulfate proteoglycans; LRP, lipoprotein receptor-related protein; TSP, thrombospondin-1; VWC, von Willebrand factor C.