The p62/MEKK3 complex in mTORC1 activation

描述(申请人提供)：研究正常细胞和肿瘤细胞如何协调生长和营养供应的机制是细胞生物学中的一个基本问题。细胞需要适应和响应营养状态的变化，以维持细胞生长和代谢动态平衡，并应对压力。解除细胞对营养物质的反应会影响肿瘤的发生，并可能成为癌症治疗的新来源。MTORC1是一种通过调节癌细胞生长和自噬等基本过程进行营养感知的中心激酶。多项研究探讨了生长因子、胰岛素和能量水平激活mTORC1的机制。然而，介导氨基酸反应的信号机制还不是很清楚。这项拨款申请是基于我们最近发表的研究结果，证明信号转导和自噬底物p62是氨基酸激活mTORC1的新的关键调节器。这一点意义重大，因为通过激活这一途径，p62调节细胞的大小和生长，并作为营养感知和自噬调节的关键节点出现，所有这些都是正常内稳态和肿瘤发生的基本事件。然而，营养物质调控mTORC1的确切机制以及p62在这一过程中的作用仍有待确定。在这方面，我们的初步数据已经确定MEKK3是mTORC1对氨基酸的反应中p62的新伙伴，以及p62被一种新的氨基酸刺激的MEKK3依赖的级联反应所磷酸化，这是其激活的关键。这项提议的长期目标是在分子和细胞水平上了解细胞翻译营养感应信号的机制，特别是那些氨基酸的信号，以激活mTORC1，这是癌症进展中的关键事件。这项应用的具体目标是严格测试这一假设，即新的p62/MEKK3复合体，以及p62对营养物质的反应而被磷酸化的能力，是通过激活mTORC1在癌症中的中心过程。这些目标将在三个具体目标中得到解决：1)确定含有PB1的MEKK3在p62调节的mTORC1激活中的作用和作用机制；2)确定p62磷酸化作为营养感受器的作用；以及3)建立新的p62-MEKK3营养传感通路在癌症中的功能作用。所有这些研究的结果将为我们理解细胞如何响应营养物质来调节其代谢和生长特性提供重要的概念性进展，这无疑将有助于设计新的癌症治疗靶点。

DESCRIPTION (provided by applicant): The study of the mechanisms whereby normal and tumor cells coordinate growth with nutrient availability is a fundamental problem in cell biology. Cells need to adapt and respond to changes in nutrient status to maintain cell growth and metabolic homeostasis, and to cope with stress. Deregulation of the cellular response to nutrients impacts tumorigenesis and can be a novel source of therapeutics in cancer. mTORC1 is a central kinase in nutrient sensing by regulating fundamental processes in cancer cell progression such as growth and autophagy. Multiple studies have addressed the mechanisms of mTORC1 activation by growth factors, insulin and energy levels. However, the signaling mechanisms mediating the amino acids response are not well understood. This grant application is based on our recently published findings demonstrating that the signaling adapter and autophagy substrate, p62, is a novel critical modulator of mTORC1 activation by amino acids. This is of great significance because by activating this pathway p62 regulates cell size and growth, and emerges as a key node in nutrient sensing and autophagy modulation, all essential events in normal homeostasis and tumorigenesis. However, the precise mechanisms of mTORC1 regulation by nutrients and the role of p62 in this process still remain to be determined. In this regard, our preliminary data have identified MEKK3 as a novel partner of p62 for mTORC1 in response to amino acids, as well as that p62 is phosphorylated by a novel amino acids-stimulated MEKK3-dependent cascade, which is critical for its activation. The long-term goal of this proposal is to understand, at a molecular and cellular level, the mechanisms whereby cells translate nutrient-sensing signals, specifically those of amino acids, for the activation of mTORC1, a critical event in cancer progression. The specific goal of this application is to rigorously test the hypothesis that the new p62/MEKK3 complex, together with the ability of p62 to get phosphorylated in response to nutrients, is a central process in cancer through the activation of mTORC1. These goals will be addressed in three specific aims: 1) Determine the role and mechanisms of action of the PB1-containing MEKK3 in p62-regulated mTORC1 activation; 2) Determine the role of p62 phosphorylation as a nutrient sensor; and 3) Establish the functional role of the novel p62-MEKK3 nutrient sensing pathway in cancer. The results of all these studies will provide significantly impactful conceptual advance to our understanding of how cells respond to nutrients to regulate their metabolic and growth properties, which undoubtedly will be instrumental in the design of new therapeutic targets in cancer.