The p62/MEKK3 complex in mTORC1 activation

描述（由申请人提供）：研究正常细胞和肿瘤细胞协调生长与营养利用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稳态，并科普压力。细胞对营养素反应的失调会影响肿瘤发生，并可能成为癌症治疗的新来源。mTORC 1是营养传感中的一种中心激酶，通过调节癌细胞进展中的基本过程，如生长和自噬。多项研究已经通过生长因子、胰岛素和能量水平解决了mTORC 1激活的机制。然而，介导氨基酸反应的信号传导机制还不清楚。这项拨款申请是基于我们最近发表的研究结果，表明信号转导衔接子和自噬底物p62是氨基酸激活mTORC 1的一种新的关键调节剂。这是非常重要的，因为通过激活这一途径，p62调节细胞大小和生长，并作为营养传感和自噬调节的关键节点出现，这些都是正常稳态和肿瘤发生中的重要事件。然而，mTORC 1的营养调控的确切机制和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MEKK 3作为mTORC 1的p62的新伴侣，对氨基酸做出反应，以及p62被新的氨基酸刺激的MEKK 3依赖性级联磷酸化，这对其激活至关重要。该提案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（特别是氨基酸信号）的机制，以激活mTORC 1，这是癌症进展中的关键事件。本申请的具体目标是严格测试新的p62/MEKK 3复合物以及p62响应营养物质而磷酸化的能力是癌症中通过mTORC 1激活的中心过程的假设。这些目标将在三个具体目标中得到解决：1）确定含有PB 1的MEKK 3在p62调节的mTORC 1活化中的作用和作用机制; 2）确定p62磷酸化作为营养传感器的作用; 3）建立新型p62-MEKK 3营养传感途径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以调节其代谢和生长特性提供具有重大影响力的概念性进展，这无疑将有助于设计癌症的新治疗靶点。

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.