The mTOR and Hippo pathway in cell growth and cancer

 描述（由申请人提供）：了解细胞生长调节的基本机制以及这种调节网络的改变如何导致癌症对于了解癌症发展和设计治疗癌症的新策略至关重要。mTORC 1和Hippo信号通路是控制细胞生长和组织/器官稳态的两个主要通路。mTORC 1是一种中央细胞生长控制器，通过刺激生物合成和抑制自噬来促进细胞生长。Hippo肿瘤抑制途径通过抑制增殖和刺激凋亡来限制组织和器官的大小。任何一种途径的失调都会导致人类癌症。因此，mTORC 1抑制剂已获得FDA批准用于癌症治疗，并且正在努力寻找可以靶向Hippo通路用于癌症适应症的药物。PI先前的工作已经揭示了mTORC 1通过生长因子调节的分子机制，以及分别通过AKT和AMPK调节细胞能量状态的分子机制。氨基酸可以说是mTORC 1最重要的刺激物。PI还将Rag GTP酶确定为氨基酸激活mTORC 1的关键介质。尽管在该领域取得了快速进展，但mTORC 1的氨基酸信号传导中的关键问题，如氨基酸传感器的性质，仍有待解决。这个R35提案的一个主要目标是阐明氨基酸激活mTORC 1的分子机制。河马途径是一个令人兴奋的新兴领域。PI的团队在建立Hippo通路的主要框架方面做出了关键贡献，包括上游信号的识别，雅普调控的生化机制，以及YAP-TEAD转录模块的演示。然而，诸如Hippo通路核心组分的调节、雅普促进肿瘤发生的分子基础以及控制器官大小的生理信号等基本问题是尚未回答的关键开放问题。这项R35提案的总体使命是在正常生理条件下获得对mTORC 1和Hippo通路的全面分子理解，并阐明这些通路的失调如何导致肿瘤发生。

 DESCRIPTION (provided by applicant): Understanding the basic mechanisms of cell growth regulation and how alteration of such regulatory networks leads to cancer is fundamentally important for understanding cancer development and designing new strategies for treating cancer. The mTORC1 and Hippo signaling pathways are two major pathways that control cell growth and tissue/organ homeostasis. mTORC1 is a central cell growth controller which promotes cell growth by stimulating biosynthesis and inhibiting autophagy. The Hippo tumor suppressor pathway limits tissue and organ size by inhibiting proliferation and stimulating apoptosis. Dysregulation of either pathway contributes to human cancer. As such, mTORC1 inhibitors have received FDA approval for cancer treatment and there is an intensive effort in searching for drugs that can target the Hippo pathway for cancer indication. Previous works from the PI have revealed the molecular mechanisms of mTORC1 regulation by growth factors and cellular energy status via AKT and AMPK, respectively. Amino acids are arguably the most important stimuli of mTORC1. The PI has also identified Rag GTPases as critical mediators of mTORC1 activation by amino acids. Despite rapid progress in the field, key issues in amino acid signaling to mTORC1, such as the nature of amino acid sensors, remain to be solved. One major goal of this R35 proposal is to elucidate the molecular mechanism of mTORC1 activation by amino acids. The Hippo pathway is an exciting emerging field. The PI's group has made key contributions in establishing the major framework of the Hippo pathway, including identification of upstream signals, the biochemical mechanism of YAP regulation, and demonstration of the YAP-TEAD transcription module. However, fundamental issues such as regulation of core Hippo pathway components, molecular basis of YAP in promoting oncogenesis, and physiological signals that control organ size are key open questions that have yet to be answered. The overall mission of this R35 proposal is to obtain a comprehensive molecular understanding of the mTORC1 and Hippo pathways under normal physiological conditions and to elucidate how dysregulation of these pathways contributes to tumorigenesis.