Eyeing the Cyr61/CTGF/NOV (CCN) group of genes in development and diseases: highlights of their structural likenesses and functional dissimilarities

Abstract

“CCN” is an acronym referring to the first letter of each of the first three members of this original group of mammalian functionally and phylogenetically distinct extracellular matrix (ECM) proteins [i.e., cysteine-rich 61 (CYR61), connective tissue growth factor (CTGF), and nephroblastoma-overexpressed (NOV)]. Although “CCN” genes are unlikely to have arisen from a common ancestral gene, their encoded proteins share multimodular structures in which most cysteine residues are strictly conserved in their positions within several structural motifs. The CCN genes can be subdivided into members developmentally indispensable for embryonic viability (e.g., CCN1, 2 and 5), each assuming unique tissue-specific functions, and members not essential for embryonic development (e.g., CCN3, 4 and 6), probably due to a balance of functional redundancy and specialization during evolution. The temporo-spatial regulation of the CCN genes and the structural information contained within the sequences of their encoded proteins reflect diversity in their context and tissue-specific functions. Genetic association studies and experimental anomalies, replicated in various animal models, have shown that altered CCN gene structure or expression is associated with “injury” stimuli—whether mechanical (e.g., trauma, shear stress) or chemical (e.g., ischemia, hyperglycemia, hyperlipidemia, inflammation). Consequently, increased organ-specific susceptibility to structural damages ensues. These data underscore the critical functions of CCN proteins in the dynamics of tissue repair and regeneration and in the compensatory responses preceding organ failure. A better understanding of the regulation and mode of action of each CCN member will be useful in developing specific gain- or loss-of-function strategies for therapeutic purposes.

Abscisic acid – an anti-angiogenic phytohormone that modulates the phenotypical plasticity of endothelial cells and macrophages

“…Vessel sprouting is initiated when ECs differentiate into tip cells (Fig. 3A), which define the direction of new sprout growth and create new connections between different sprouts to generate an interconnected and functional vascular network (Chaqour, 2013;Krupska et al, 2015). Intravitreal injection of ABA resulted in the alteration of tip cell shape and morphology.…”

Targeting molecules to medicine with mTOR, autophagy and neurodegenerative disorders

“…EPO requires Wnt signalling to block ‘pro‐apoptotic’ forkhead transcription factor activity that can result in cell death . A downstream target in the Wnt pathway also linked to mTOR is the Wnt1 inducible signalling pathway protein one (WISP1) , a member of the six secreted extracellular matrix associated CCN family of proteins . WISP1 activates mTOR, inhibits PRAS40 and limits TSC2 activity to increase microglial cell survival during oxidative stress and Aβ toxicity.…”

Periostin is required for matricellular localization of CCN3 in periodontal ligament of mice

“…2a; Krupska et al 2015). To investigate the binding domain of CCN3 to periostin, we designed the CCN3 deletion constructs shown in Fig.…”