Role of TGF-b-induced Shc-Erk MAPK signaling in epithelial-mesenchymal transition

描述(申请人提供)：癌细胞的上皮向间充质转化(EMT)被认为是癌症侵袭的基础，也是癌症干细胞特性的基础，因此是癌症进展的重要步骤。已有研究表明，转化生长因子-ss可诱导内皮细胞转化，癌细胞产生的转化生长因子-生长因子增加，导致自分泌转化生长因子-生长因子信号增强，被认为是启动和推动肿瘤侵袭和转移的始动因素。转化生长因子-ss通过跨膜蛋白的异构体复合体激活Smads作为转录效应器来调节基因表达，以及几个非Smad途径，如Erk MAP激酶和PI3激酶-Akt-Tor通路。虽然Smads调节与EMT相关的基因表达程序，但转化生长因子-b诱导的Erk MAP激酶信号在EMT中的作用尚不清楚。我们的实验室最近发现，I型转化生长因子-生长因子受体(TssRI)是一种双特异性的激酶，在转化生长因子-生长因子的作用下，酪氨酸上的SHCA被磷酸化，而转化生长因子-生长因子诱导SHCA重新聚集到TssRI上，导致TssRI在Tyr和主要是Ser上的SHCA的磷酸化。TssRI对SHCA的募集和Tyr的磷酸化是转化生长因子-ss诱导的ERK-MAP信号转导所必需的。我现在提出一个研究项目，以进一步确定SHCA和TBRI在应对转化生长因子-生长因子-生长因子的反应中的相互作用，并评价转化生长因子-生长因子-生长因子诱导的SHCA募集和ERK-MAP激酶信号在转化生长因子-生长因子-生长因子诱导的子宫内膜转化和侵袭中的作用。作为这项研究的一部分，我还旨在研究SHCA的Tyr和Ser磷酸化在转化生长因子-ss诱导的Erk MAP激酶信号转导和EMT中的相对作用。我们的结果不仅有助于更好地理解转化生长因子-ss信号转导的机制，而且有助于了解转化生长因子-生长因子信号转导在EMT和癌细胞侵袭中的作用。) 公共卫生相关性：肿瘤对其他组织的侵袭是癌症患者死亡的主要原因。转化生长因子-2是一种由肿瘤细胞分泌的蛋白质，它向肿瘤细胞发出信号，使其在形态和行为上发生变化，并允许它们侵袭和扩散到其他组织。这项拟议的研究旨在更好地了解当转化生长因子-SS作用于细胞时激活的分子通路和信号，以及它们在癌细胞行为、癌症进展和转移中的作用。这项工作可能会确定癌症治疗的新靶点。)

DESCRIPTION (provided by applicant): Epithelial-to-mesenchymal transition (EMT) of carcinoma cells is thought to be at the basis of cancer invasion, and of the properties of carcinoma stem cells, and is therefore an important step in cancer progression. TGF-ss has been shown to induce EMT, and increased production of TGF-ss by cancer cells, resulting in increased autocrine TGF-ss signaling, is thought to initiate and drive cancer invasion and metastasis. TGF-ss signals through a heteromeric complex of transmembrane kinases that then activate Smads as transcription effectors that regulate gene expression, and several non-Smad pathways such as the Erk MAP kinase and PI3 kinase-Akt-TOR pathways. Whereas Smads regulate the gene expression program associated with EMT, the role of TGF-b-induced Erk MAP kinase signaling in EMT is unknown. Our lab recently showed that the type I TGF-ss receptor, TssRI, is a dual specificity kinase that becomes phosphorylated on Tyr in response to TGF-ss, and that TGF-ss induces the recruitment of ShcA to TssRI, resulting in ShcA phosphorylation by TssRI on Tyr and predominantly Ser. The recruitment and Tyr phosphorylation of ShcA by TssRI are required for TGF-ss-induced Erk MAP kinase signaling. I now propose a research project to further define the interaction of ShcA with TbRI in response to TGF-ss, and to evaluate the role of TGF-ss-induced ShcA recruitment and Erk MAP kinase signaling in TGF-ss-induced EMT and invasion. As part of this study I also aim to address the relative contributions of Tyr versus Ser phosphorylation of ShcA in TGF-ss-induced Erk MAP kinase signaling and EMT. Our results should lead to a better understanding of not only the mechanisms of TGF-ss signaling, but also the roles of TGF-ss signaling in EMT and cancer cell invasion. ) PUBLIC HEALTH RELEVANCE: Tumor invasion to other tissues is the primary cause of mortality in cancer patients. TGF-2, a protein that is secreted by tumor cells, signals the tumor cells to change in morphology and behavior, and allows them to invade and spread to other tissues. The proposed research aims to better understand the molecular pathways and signals that are activated when TGF-ss acts on cells, and their roles in cancer cell behavior, cancer progression and metastasis. This work may identify new targets for cancer therapy. )