A working model for CCN3 C-terminal domain-mediated transcriptional modulation of the plasminogen activation system

Over the past 2 decades, major advances have contributed to the elucidation of the structural and biochemical bases underlying the biological activities attributed to CCN proteins. The concept that CCN proteins exhibit bifunctional "moonlighting" properties in both the extracellular matrix (ECM) and the cell nucleus has recently emerged. CCN proteins participate in dual signaling processes, integrating combinatorial interactions with regulatory ligands, cell surface receptors or associated co-receptors such as heparan sulfate proteoglycans (HSPGs), LRPs, TrkA, Notch, integrins, BMP-4, TGF-β, and FGFR2, as well as transcription factors in the nuclear compartment. In this manuscript, we propose an exploratory integrative model that brings together previously unassociated observations into a coherent framework. In this model, the C-terminal module, present in all CCN proteins except CCN5, is proposed to direct the formation of homo- and heterodimers, which constitute a fundamental level of transcriptional regulation.