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

描述（由申请人提供）：癌细胞的上皮到间充质转化（EMT）被认为是癌症侵袭的基础，也是癌症干细胞的特性，因此是癌症进展的重要步骤。TGF-ss已被证明可以诱导EMT，而癌细胞TGF-ss的产生增加，导致自分泌TGF-ss信号的增加，被认为可以启动和驱动癌症的侵袭和转移。TGF-ss通过跨膜激酶的异质复合体发出信号，然后激活smad作为调节基因表达的转录效应器，以及几种非smad途径，如Erk MAP激酶和PI3激酶- akt - tor途径。虽然Smads调节与EMT相关的基因表达程序，但tgf -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TGF-ss受体TssRI是一种双特异性激酶，在TGF-ss的作用下在Tyr上磷酸化，TGF-ss诱导ShcA向TssRI募集，导致TssRI在Tyr上磷酸化ShcA，主要是在Ser上磷酸化ShcA。TssRI对ShcA的募集和Tyr磷酸化是tgf -ss诱导的Erk MAP激酶信号传导所必需的。我现在提出一个研究项目，以进一步确定ShcA与TbRI在TGF-ss反应中的相互作用，并评估TGF-ss诱导的ShcA募集和Erk MAP激酶信号在TGF-ss诱导的EMT和侵袭中的作用。作为本研究的一部分，我还旨在探讨Tyr与ShcA的Ser磷酸化在tgf -ss诱导的Erk MAP激酶信号传导和EMT中的相对贡献。我们的研究结果不仅有助于更好地理解TGF-ss信号传导的机制，还有助于更好地理解TGF-ss信号传导在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. )