MET and p66SHC interactomes and functions

消化道的肠上皮的完整性通过其快速更新来确保。这涉及各种肠上皮细胞（IEC）的时空协调增殖、迁移、分化和存活。这些细胞过程由IEC和相邻细胞产生的生长因子信号决定。肝细胞生长因子（HGF）是一种通过激活上皮细胞中受体酪氨酸激酶（RTK）MET促进和维持各种器官组织结构的分子。有证据表明MET/HGF受体轴在肠上皮细胞的更新中起着关键作用，但由于缺乏HGF或MET的小鼠胚胎早期死亡，MET的研究受到很大限制。MET被激活后，可形成信号多蛋白复合物，将下游调节信号传递到多种生物学过程。我们以前的工作确定，MET激活培养的IEC刺激几个过程的肠上皮细胞的更新至关重要。此外，我们发现了MET与其一些相互作用伙伴之间相互作用的新的非经典动力学机制（最显著的是p66 SHC），导致多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。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中的全局和上下文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p66 SHC在肠上皮更新中的信号网络整合中的IEC特异性作用。肠类器官代表了用于肠上皮分子研究的最先进的体外系统。类器官紧密复制肠上皮组织以及参与肠细胞分化、功能和更新的许多生物学过程。定义MET/p66 SHC复合物在细胞中的动态时空调节及其相互作用组的性质，必将提供对MET信号传导及其在IEC生物学中的背景功能的无与伦比的理解。这些新的见解也可以作为一个更广泛的理解的信号网络和其他RTK的功能的范例，因为许多RTK的信号遵循相同的一般生物学原理。

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.