pappalysin金属蛋白酶,PAPP-A和PAPP-A2已经成为参与调节胰岛素样生长因子(IGF)信号传导的高度特异性蛋白水解酶。唯一已知的pappalysin底物是IGF结合蛋白(IGFBP)的子集,它们以高亲和力结合IGF-I或IGF-II以拮抗受体结合。因此,通过切割IGFBPs,pappalysins具有增加IGF生物活性并因此促进IGF信号传导的潜力。这与系统和局部IGF调节有关,在正常和几种病理生理条件下。最近发现Stiniocalcin-1和-2是有效的pappalysin抑制剂,因此包含完整蛋白水解系统的缺失成分,Stiniocalcin-PAPP-A-IGFBP-IGF轴。这里,我们提供了理解这种分子网络特性所必需的生物学背景,我们回顾生化数据,动物实验,临床资料,和遗传数据支持该分支的生理操作,作为IGF系统的重要组成部分。然而,尽管体内数据清楚地表明了它的力量,了解其微妙的操作是一个挑战,例如,多重平衡和抑制动力学可以决定如何,where,当IGF受体受到刺激时。此外,实际上,所有的调节蛋白具有怀疑的或已知的与IGF信号传导不直接相关的活性。这些活动如何与IGF信号传导整合在未来也是重要的。
The pappalysin metalloproteinases, PAPP-A and PAPP-A2, have emerged as highly specific proteolytic enzymes involved in the regulation of insulin-like growth factor (IGF) signaling. The only known pappalysin substrates are a subset of the IGF binding proteins (IGFBPs), which bind IGF-I or IGF-II with high affinity to antagonize receptor binding. Thus, by cleaving IGFBPs, the pappalysins have the potential to increase IGF bioactivity and hence promote IGF signaling. This is relevant both in systemic and local IGF regulation, in normal and several pathophysiological conditions. Stanniocalcin-1 and -2 were recently found to be potent pappalysin inhibitors, thus comprising the missing components of a complete proteolytic system, the stanniocalcin-PAPP-A-IGFBP-IGF axis. Here, we provide the biological context necessary for understanding the properties of this molecular network, and we review biochemical data, animal experiments, clinical data, and genetic data supporting the physiological operation of this branch as an important part of the IGF system. However, although in vivo data clearly illustrate its power, it is a challenge to understand its subtle operation, for example, multiple equilibria and inhibitory kinetics may determine how, where, and when the IGF receptor is stimulated. In addition, literally all of the regulatory proteins have suspected or known activities that are not directly related to IGF signaling. How such activities may integrate with IGF signaling is also important to address in the future.