MET and p66SHC interactomes and functions

消化道肠上皮的快速更新保证了其完整性。这涉及多种肠上皮细胞（IEC）的时空协调增殖、迁移、分化和存活。这些细胞过程是由内皮细胞和邻近细胞产生的生长因子信号决定的。肝细胞生长因子（HGF）是一种通过激活上皮细胞中的受体酪氨酸激酶（RTK） MET来促进和维持各器官组织组织的分子。一些证据表明MET/HGF受体轴可能在肠上皮的更新中起关键作用，但HGF或MET缺乏小鼠的早期胚胎死亡极大地限制了其研究。******当被激活时，MET形成信号多蛋白复合物，可以将下游调节信号传递到各种生物过程。我们之前的研究发现，培养的IECs中的MET激活刺激了肠上皮更新的几个关键过程。此外，我们发现了MET与其一些相互作用伙伴（最明显的是p66SHC）之间相互作用的新的非规范动态机制，导致各种可能的相互作用复合物和影响MET调节IEC存活、增殖和迁移的生物学结果。******在这里，我们建议利用肠道类器官技术结合高度复杂的高通量筛选方法来分析IEC中全局和上下文MET多蛋白复合物。这些研究将有助于了解MET及其相互作用伙伴p66SHC在肠上皮更新信号网络整合中的iec特异性作用。肠道类器官代表了肠上皮分子研究中最先进的体外系统。类器官密切复制肠上皮组织以及肠细胞分化、功能和更新的许多生物学过程。******定义细胞中MET/p66SHC复合物的动态时空调控及其相互作用组的性质必然会提供对MET信号传导及其在IEC生物学中的上下文功能的无与伦比的理解。鉴于许多rtk的信号传导遵循相同的一般生物学原理，这些新颖的见解也可以作为更广泛理解其他rtk的信号网络和功能的范例。

The integrity of the intestinal epithelium of the digestive tract is ensured by its rapid renewal. This involves spatiotemporal coordinated proliferation, migration, differentiation and survival of various intestinal epithelial cells (IEC). These cellular processes are dictated by growth factor signals produced by IECs and adjacent cells. Hepatocyte growth factor (HGF) is a molecule promoting and maintaining tissue organization in various organs by activating the receptor tyrosine kinase (RTK) MET in epithelial cells. Several lines of evidence suggest that the MET/HGF receptor axis may play a key role in the renewal of the intestinal epithelium, but the early embryonic death of HGF- or MET-deficient mice have greatly limited its study.******When activated, MET forms signaling multiprotein complexes that may relay downstream regulatory signals to a variety of biological processes. Our previous work identified that MET activation in cultured IECs stimulates several processes critical for the renewal of the intestinal epithelium. Moreover, we uncovered novel non-canonical dynamic mechanisms of interaction between MET and some of its interacting partners (most notably p66SHC), resulting in a variety of possible interaction complexes and biological outcomes affecting MET regulation of IEC survival, proliferation and migration.******Here, we propose to exploit the intestinal organoid technology combined with highly-sophisticated high-throughput screening methods to analyze the global and contextual MET multiprotein complexes in IEC. These studies will help understand the IEC-specific role of MET and its interacting partner p66SHC in the signaling network integration operating in the renewal of the intestinal epithelium. Intestinal organoids represent the most advanced in vitro system for molecular studies of the intestinal epithelium. Organoids closely replicate the intestinal epithelium organization as well as many of the biological processes involved on intestinal cells differentiation, function and renewal. ******Defining the dynamic spatiotemporal regulation of MET/p66SHC complexes in cells and the nature of their interactomes is bound to provide an unparalleled understanding of MET signaling and its contextual functions in the biology of IEC. These novel insights may also serve as a paradigm for a more generalized understanding of the signaling networks and functions of other RTKs, given that signaling by many RTKs follows the same general biological principles.