Structural insights into regulation of CCN protein activities and functions

Abstract

CCN proteins play important functions during development, in repair mechanisms following tissue injury, as well as in pathophysiologic mechanisms of metastasis of cancer. CCNs are secreted proteins that have a multimodular structure and are categorized as matricellular proteins. Although the prevailing view is that CCN proteins regulate biologic processes by interacting with a wide array of other proteins in the microenvironment of the extracellular matrix, the molecular mechanisms of action of CCN proteins are still poorly understood. Not dissuading the current view, however, the recent appreciation that these proteins are signaling proteins in their own right and may even be considered preproproteins controlled by endopeptidases to release a C-terminal bioactive peptide has opened new avenues of research. Also, the recent resolution of the crystal structure of two of the domains of CCN3 have provided new knowledge with implications for the entire CCN family. These resolved structures in combination with structural predictions based upon the AlphaFold artificial intelligence tool provide means to shed new light on CCN functions in context of the notable literature in the field. CCN proteins have emerged as important therapeutic targets in several disease conditions, and clinical trials are currently ongoing. Thus, a review that critically discusses structure - function relationship of CCN proteins, in particular as it relates to interactions with other proteins in the extracellular milieu and on the cell surface, as well as to cell signaling activities of these proteins, is very timely. Graphical abstract Suggested mechanism for activation and inhibition of signaling by the CCN protein family (graphics generated with BioRender.com).

Role for CCN1 in lysophosphatidic acid response in PC‐3 human prostate cancer cells

“…The role of CCN2, which is also induced by LPA, was not tested in the current study; we acknowledge that CCN1 and CCN2 share some functionalities and that both proteins are likely important to LPA response. In addition, CCN1 and CCN2 are proteolyzed to generate fragments with bioactivity 85 ; this aspect was not examined in our study. Potential interactions between CCN1 and CCN2, and between their proteolysis products, add complexity when both proteins are induced by the same stimulus.…”

Involvement of Matricellular Proteins in Cellular Senescence: Potential Therapeutic Targets for Age-Related Diseases

“…CCN2 is additionally called connective tissue growth factor (CTGF) and IGFBP-8 [ 63 ]. CCN2 is expressed in a variety of tissues at the development stages, with particularly high levels in cartilage and vasculature [ 64 ], and its expression is maintained in normal adult tissues [ 59 , 65 ].…”

“…CCN3, also known as nephroblastoma overexpressed (NOV) and IGFBP-9 [ 63 , 72 ], is highly expressed in adult endotheliocytes, smooth muscle cells, fibroblasts, and chondrocytes [ 73 ]. Several studies have detected dysregulated expression of CCN3 in aging [ 32 ] and a variety of age-related diseases, including OA [ 74 ].…”

“…Jun and Lau have found that, similar to CCN1 [23], CCN2 also induces fibroblast senescence by binding to integrin α6β1, revealing that CCN2-induced fibroblast senescence concurrently restrains fibrotic responses [24]. CCN3, also known as nephroblastoma overexpressed (NOV) and IGFBP-9 [63,72], is highly expressed in adult endotheliocytes, smooth muscle cells, fibroblasts, and chondrocytes [73]. Several studies have detected dysregulated expression of CCN3 in aging [32] and a variety of age-related diseases, including OA [74].…”