Leask Andrew, Abraham David J
CIHR Group in Skeletal Development and Remodeling, Division of Oral Biology, and Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON N6A 5C1, Canada.
J Cell Sci. 2006 Dec 1;119(Pt 23):4803-10. doi: 10.1242/jcs.03270.
The CCN family is a group of six secreted proteins that specifically associate with the extracellular matrix. Structurally, CCN proteins are modular, containing up to four distinct functional domains. CCN family members are induced by growth factors and cytokines such as TGFbeta and endothelin 1 and cellular stress such as hypoxia, and are overexpressed in pathological conditions that affect connective tissues, including scarring, fibrosis and cancer. Although CCN family members were discovered over a decade ago, the precise biological role, mechanism of action and physiological function of these proteins has remained elusive until recently, when several key mechanistic insights into the CCN family emerged. The CCNs have been shown to have key roles as matricellular proteins, serving as adaptor molecules connecting the cell surface and extracellular matrix (ECM). Although they appear not to have specific high-affinity receptors, they signal through integrins and proteoglycans. Furthermore, in addition to having inherent adhesive abilities that modulate focal adhesions and control cell attachment and migration, they execute their functions by modulating the activity of a variety of different growth factors, such as TGFbeta. CCN proteins not only regulate crucial biological processes including cell differentiation, proliferation, adhesion, migration, apoptosis, ECM production, chondrogenesis and angiogenesis, but also have more sinister roles promoting conditions such as fibrogenesis.
CCN家族是一组由六种分泌蛋白组成的蛋白,它们特异性地与细胞外基质结合。从结构上看,CCN蛋白是模块化的,包含多达四个不同的功能域。CCN家族成员由生长因子和细胞因子(如转化生长因子β和内皮素1)以及细胞应激(如缺氧)诱导产生,并且在影响结缔组织的病理状况(包括瘢痕形成、纤维化和癌症)中过表达。尽管CCN家族成员在十多年前就已被发现,但直到最近出现了一些关于CCN家族的关键机制见解之前,这些蛋白的确切生物学作用、作用机制和生理功能一直难以捉摸。CCN已被证明作为基质细胞蛋白发挥关键作用,充当连接细胞表面和细胞外基质(ECM)的衔接分子。尽管它们似乎没有特定的高亲和力受体,但它们通过整合素和蛋白聚糖发出信号。此外,除了具有调节粘着斑、控制细胞附着和迁移的固有粘附能力外,它们还通过调节多种不同生长因子(如转化生长因子β)的活性来执行其功能。CCN蛋白不仅调节包括细胞分化、增殖、粘附、迁移、凋亡、ECM产生、软骨形成和血管生成等关键生物学过程,而且在促进诸如纤维化形成等状况方面具有更有害的作用。