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

描述（由申请人提供）：癌细胞的上皮-间充质转化（EMT）被认为是癌症侵袭和癌干细胞特性的基础，因此是癌症进展的重要步骤。TGF-β已显示诱导EMT，并且癌细胞增加TGF-β的产生，导致增加的自分泌TGF-β信号传导，被认为引发和驱动癌症侵袭和转移。TGF-β通过跨膜激酶的异聚体复合物发出信号，然后激活Smads作为调节基因表达的转录效应子，以及几种非Smad途径，如Erk MAP激酶和PI 3激酶-Akt-TOR途径。尽管Smads调节与EMT相关的基因表达程序，但TGF-β诱导的Erk MAP激酶信号传导在EMT中的作用尚不清楚。我们的实验室最近表明，I型TGF-β受体TssRI是一种双重特异性激酶，其响应于TGF-β而在Tyr上磷酸化，并且TGF-β诱导ShcA向TssRI的募集，导致TssRI在Tyr和主要是Ser上对ShcA的磷酸化。TssRI对ShcA的募集和Tyr磷酸化是TGF-β诱导的Erk MAP激酶信号传导所需的。我现在提出一个研究项目，以进一步确定的相互作用的ShcA与TbRI在响应TGF-β，并评估TGF-β诱导的ShcA招聘和Erk MAP激酶信号在TGF-β诱导的EMT和入侵的作用。作为这项研究的一部分，我还旨在解决相对贡献的酪氨酸与丝氨酸磷酸化的ShcA在TGF-β诱导的ERK MAP激酶信号和EMT。我们的研究结果不仅有助于更好地理解TGF-β信号转导的机制，而且有助于更好地理解TGF-β信号转导在EMT和癌细胞侵袭中的作用。)

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. )