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CCN3 and Calcium Signaling Alain Lombet1, Nathalie Planque2, Anne-Marie Bleau2, Chang Long Li2 and Bernard Perbal*2

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CCN3 and Calcium Signaling Alain Lombet1, Nathalie Planque2, Anne-Marie Bleau2, Chang Long Li2 and Bernard Perbal*2 Cell Communication and Signaling BioMed Central Review Open Access CCN3 and calcium signaling Alain Lombet1, Nathalie Planque2, Anne-Marie Bleau2, Chang Long Li2 and Bernard Perbal*2 Address: 1CNRS UMR 8078, Hôpital Marie Lannelongue, 133, Avenue de la Résistance 92350 Le PLESSIS-ROBINSON, France and 2Laboratoire d'Oncologie Virale et Moléculaire, Tour 54, Case 7048, Université Paris 7-D.Diderot, 2 Place Jussieu 75005 PARIS, France Email: Alain Lombet - [email protected]; Nathalie Planque - [email protected]; Anne-Marie Bleau - [email protected]; Chang Long Li - [email protected]; Bernard Perbal* - [email protected] * Corresponding author Published: 15 August 2003 Received: 26 June 2003 Accepted: 15 August 2003 Cell Communication and Signaling 2003, 1:1 This article is available from: http://www.biosignaling.com/content/1/1/1 © 2003 Lombet et al; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL. Abstract The CCN family of genes consists presently of six members in human (CCN1-6) also known as Cyr61 (Cystein rich 61), CTGF (Connective Tissue Growth Factor), NOV (Nephroblastoma Overexpressed gene), WISP-1, 2 and 3 (Wnt-1 Induced Secreted Proteins). Results obtained over the past decade have indicated that CCN proteins are matricellular proteins, which are involved in the regulation of various cellular functions, such as proliferation, differentiation, survival, adhesion and migration. The CCN proteins have recently emerged as regulatory factors involved in both internal and external cell signaling. CCN3 was reported to physically interact with fibulin-1C, integrins, Notch and S100A4. Considering that, the conformation and biological activity of these proteins are dependent upon calcium binding, we hypothesized that CCN3 might be involved in signaling pathways mediated by calcium ions. In this article, we review the data showing that CCN3 regulates the levels of intracellular calcium and discuss potential models that may account for the biological effects of CCN3. Review sidered that cell populations function as « societies » and Introduction that intercellular communication is pivotal to harmoni- The control of normal cell biology, from life to death ous development during life and to intracellular biologi- involves an extremely complex array of interconnected cal modifications leading to cell death. Efficient signaling pathways, which govern inward and outward coordination is an absolute requirement to safe communication. Over the two past decades, a plethora of functioning proteins have been found to participate in these funda- mental regulatory circuits. In most cases, alterations of sig- It is critical to study and understand cross talking in cell naling result in pathological conditions. For example, population and to identify messengers that allow inte- many of the proteins discovered as oncogenes and tumor grated responses. Unfortunately, very little is known pres- suppressors in cancer cells were shown to be key signaling ently about the processes that coordinate the various molecules. cellular signaling pathways. Signaling is pivotal to the coordinated response of cells in An increasing amount of data points to matricellular pro- tissues and organs within the whole body. It is often con- teins as major players in global control. Members of the Page 1 of 10 (page number not for citation purposes) Cell Communication and Signaling 2003, 1 http://www.biosignaling.com/content/1/1/1 CCN family of proteins have recently emerged as impor- Considering the variety of sometimes opposite biological tant matricellular regulatory factors involved in both functions attributed to the CCN proteins and the tight internal and external cell signaling. spatio-temporal regulation of their expression in many tissues of different origins, we proposed that the CCN pro- The CCN family of proteins teins interact with several different partners and that the Bork coined the CCN acronym in 1993 [1], soon after our resulting combinatorial events are responsible for the discovery of a new gene –nov– presently designated CCN3 variety of their functions [7]. [2] whose expression was enhanced in all myeloblastosis associated virus (MAV)-induced nephroblastomas [3], CCN3 interacts with several different proteins which represent a unique animal model of the Wilms' To identify the potential partners of CCN3, we first used tumor in human [4]. the yeast two-hybrid strategy [11,12]. Two types of consid- erations dictated our choice of the full length CCN3 pro- Analysis of the predicted primary structure of CCN3 indi- tein as bait. Firstly, each individual module was cated that it was structurally related to two other proteins potentially interacting with several factors whose partici- (CYR61/CCN1 and CTGF/CCN2) that had been previ- pation is essential to the biological functions of the fami- ously described as « immediate early » proteins showing lies of proteins that contain these modules. Therefore, mitogenic activities. The concept of a protein family was interaction with many of the potential interactions taking sustained by the fact that these three proteins were sharing place with individual modules might not be directly rele- a common mosaic organization with four structural mod- vant to the functions of CCN3. Secondly, and more ules sharing identity with Insulin like growth factor (IGF)- importantly, some interactions critical for the functions of binding proteins (IGFBPs), Von Willebrand factor type C CCN3 might require the tertiary structure of the full- repeat, thrombospondin type 1 repeat, and secreted regu- length protein. latory factors containing a cystin knot motif involved in dimerization. Several different proteins were found to physically interact with CCN3 in the yeast assay especially fibulin-1C, The discovery of CCN3 provided the first evidence for a integrins, Notch and S100A4 [7]. The physical interaction member of the CCN family of proteins showing antipro- of CCN3 with these proteins has been checked either by liferative activity on chicken embryo fibroblasts (CEF). GST-pull down assay, co-immunprecipitation, co-immu- Interestingly, the aminotruncated version of CCN3 nolocalization, or functional interdependence. The pro- expressed in one MAV-induced nephroblastoma was stim- teins interacting with CCN3 were either secreted, or ulating growth and inducing morphological transforma- localized in the cytosol, or localized in the nucleus of var- tion of the CEF [3]. ious cell types. Since then, three new members of the CCN family have In as much as the conformation and biological activity of been identified. CCN4 and CCN5, which were originally fibulin-1C, integrins, Notch and S100A4 were dependent designated elm1 and rCOP1 respectively [5,6], were also upon calcium, we hypothesized that CCN3 might be described as rodent proteins devoted of an antiprolifera- involved in signaling pathways involving calcium ions. tive activity. Their human counterpart were identified a few years later as WINT-induced secreted proteins (WISP), Considering the considerable importance of calcium as a with a new member (CCN6) originally identified from second messenger, these observations open new avenues EST libraries and designated WISP3. for understanding the role of CCN proteins in cell growth regulation. All CCN proteins except CCN5 – which lacks the CT mod- ule – show a similar multimodular organization. CCN3-Fibulin-1C and calcium Yeast two-hybrid screens indicated that CCN3 interacted The ccn genes are expressed in a wide variety of tissues. with the calcium-binding extracellular matrix glycopro- Expression of CCN proteins has been associated to several tein fibulin-1C [11]. Fibulin-1C is associated with various fundamental biological processes such as angiogenesis, connective tissues, basement membranes and blood; it chondrogenesis, wound healing [7–9]; their expression is was also reported to interact with extracellular matrix pro- detected during muscular differentiation, nervous system teins such as fibronectin, laminin, and fibrinogen [13]. development and bone remodeling with an enhancement Although a distinct function for fibulin-1C has not yet of CTGF correlated to several fibrotic situations [7–9]. been described, evidence has emerged to indicate that it Aberrant ccn gene expression is also associated to tumori- may regulate cell adhesion and migration along protein genesis [10], and has been shown to provide useful mark- fibers within the extracellular matrix and play a role in ers for tumor typing and prognosis. homeostasis and thrombosis [14]. Moreover, fibulin-1C Page 2 of 10 (page number not for citation purposes) Cell Communication and Signaling 2003, 1 http://www.biosignaling.com/content/1/1/1 exhibits calcium-dependent binding and its functions the two subunits. Furthermore, the binding of Ca2+ to a were reported to dependent upon the calcium binding high affinity site seems to be necessary for ligand binding. [11]. It was recently shown that CCN3 physically interacts with The identification of an interaction between fibulin-1C integrins αVβ3 and α5β1 [21]. CCN3 acts on endothelial and CCN3 provides clue for possible interaction of CCN cells to stimulate pro-angiogenic activities, and supports in signaling pathways involving extracellular matrix, cell migration and adhesion through different cell surface cytoskeleton proteins and
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