The mTOR and Hippo pathway in cell growth and cancer

 描述(申请人提供)：了解细胞生长调控的基本机制以及这种调控网络的改变如何导致癌症，对于了解癌症的发展和设计新的癌症治疗策略至关重要。MTORC1和Hippo信号通路是控制细胞生长和组织/器官动态平衡的两条主要通路。MTORC1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。河马肿瘤抑制途径通过抑制增殖和刺激细胞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，mTORC1抑制剂已获得FDA批准用于癌症治疗，并正在加紧努力寻找能够针对河马途径的癌症适应症的药物。以往的PI工作分别揭示了生长因子调节mTORC1的分子机制和通过AKT和AMPK调节细胞能量状态的分子机制。氨基酸可以说是mTORC1最重要的刺激因素。PI还发现Rag GTP酶是氨基酸激活mTORC1的关键介质。尽管这一领域取得了快速进展，但氨基酸信号转导mTORC1的关键问题，如氨基酸传感器的性质，仍有待解决。R35提案的一个主要目标是阐明氨基酸激活mTORC1的分子机制。河马路径是一个令人兴奋的新兴领域。Pi的小组在建立河马途径的主要框架方面做出了关键贡献，包括上游信号的鉴定，YAP调控的生化机制，以及YAP-tead转录模块的演示。然而，诸如河马核心途径成分的调控、YAP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仍然是尚未回答的关键问题。R35提案的总体任务是从分子上全面了解正常生理条件下的mTORC1和河马通路，并阐明这些通路的失调是如何导致肿瘤发生的。

 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.