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. 2013 Aug;7(3):169-77.
doi: 10.1007/s12079-013-0193-7. Epub 2013 Feb 19.

CCN proteins: A centralized communication network

Bernard Perbal  1
Affiliations

CCN proteins: A centralized communication network

Bernard Perbal. J Cell Commun Signal. 2013 Aug.

Abstract

The CCN family of proteins includes six members presently known as CCN1, CCN2, CCN3, CCN4, CCN5 and CCN6. These proteins were originally designated CYR61, CTGF, NOV, and WISP-1, WISP-2, WISP-3. Although these proteins share a significant amount of structural features and a partial identity with other large families of regulatory proteins, they exhibit different biological functions. A critical examination of the progress made over the past two decades, since the first CCN proteins were discovered brings me to the conclusion that most of our present knowledge regarding the functions of these proteins was predicted very early after their discovery. In an effort to point out some of the gaps that prevent us to reach a comprehensive view of the functional interactions between CCN proteins, it is necessary to reconsider carefully data that was already published and put aside, either because the scientific community was not ready to accept them, or because they were not fitting with the « consensus » when they were published. This review article points to avenues that were not attracting the attention that they deserved. However, it is quite obvious that the six members of this unique family of tetra-modular proteins must act in concert, either simultaneously or sequentially, on the same sites or at different times in the life of living organisms. A better understanding of the spatio-temporal regulation of CCN proteins expression requires considering the family as such, not as a set of single proteins related only by their name. As proposed in this review, there is enough convincing pieces of evidence, at the present time, in favor of these proteins playing a role in the coordination of multiple signaling pathways, and constituting a Centralized Communication Network. Deciphering the hierarchy of regulatory circuits involved in this complex system is an important challenge for the near future. In this article, I would like to briefly review the concept of a CCN family of proteins and critically examine the progress made over the past 10 years in the understanding of their biological functions and involvement in both normal and pathological processes.

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Figures

Fig. 1
Fig. 1
The prototypic CCN3 protein. The schematic organization of CCN3 exons on the human genome is represented with the corresponding structural domains contained in the full length version of CCN3. SP is for signal peptide. Salient features of CCN proteins are also indicated. See text for details
Fig. 2
Fig. 2
The CCN family of porteins in human
Fig. 3
Fig. 3
Model for homotypic and heterotypic interactions. CCN proteins can make use of their CT and VWC domains to interact with other proteins harboring the same type of domains. Proteins lacking one or more of these domains may act as dominant negative. The importance of these potential interactions should be considered in the context of previously reported CCN isoforms lacking domains (Perbal 2009). Non-CCN proteins with CT-like structure can also interact with CCN proteins. This type of interaction is proposed to account for the transport of CCN3 to the nucleus
Fig. 4
Fig. 4
Schematic drawing of CCN proteins partners. Interactions of CCN proteins with other ligands and regulators are shown here to occur in the extracellular matrix, at the cell membrane and inside the cytoplasm and the nucleus of cells
Fig. 5
Fig. 5
Inhibition of cell proliferation by CCN3 results from a break at the S/G2 transition in the cell cycle. Synchronized cells that express CCN3 accumulate at the S phase. As a result the cells go less efficiently through the cycle. Data are from Bleau et al. (see text)
Fig. 6
Fig. 6
The C-terminal half of CCN3 is sufficient to promote antiproliferative activity. The drawing show the growth curves of stably transfected cell lines constructs expressing either the full length CCN3 protein CMV47 and G59-540, the three first domains of CCN3 (NH35), or the C-terminal half of CCN3 (NH45). All constructs induce a dramatic inhibition of cell proliferation. The effects obtained with the NH45 transfected cells indicated that the inhibitory potential is contained within the last two domains of CCN3. Data are fom Bleau et al. (see text)
Fig. 7
Fig. 7
A model for the CCN Centralized Communication Network. In this model, CCN proteins constitute the control center of a complex array of interactions which are part of several signaling pathways whose action must be tightly coordinated to provoke responses that must be adapted to the variations of the surrounding microenvironment and on another scale, to the variations of the outside medium in which organisms evolve. The coordination of these pathways by CCN proteins is based on functional interactions that have been reported for example with Integrins, Bone Morphogenic Proteins, Notch1, Calcium channels, fibulin 1C, Wnt, Heparan sulfate proteoglycans, decorin, TGFbeta, Tyrosine receptor kinase A, Low-density lipoprotein receptor related protein, and CCN proteins themselves
Fig. 8
Fig. 8
An artistic representation of the Centralized Communication Network (CCN)
See this image and copyright information in PMC

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