The p62/MEKK3 complex in mTORC1 activation

mTORC1 激活中的 p62/MEKK3 复合物

基本信息

批准号：
9042999
负责人：
Maria Teresa Diaz Meco Conde
金额：
$ 44.61万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9042999
关键词：
Address Amino Acids Amino Acids Activation Applications Grants Autophagocytosis Binding Biological Cancer Biology Cancer Cell Growth Cell Culture Techniques Cell Proliferation Cell Size Cell physiology Cells Cellular biology Complex Data Event FRAP1 gene Future Goals Growth Health Homeostasis Human Insulin Knockout Mice Knowledge Light Link Lysosomes Malignant Neoplasms Mediating Metabolic Metabolic Diseases Modeling of Functional Interactions Molecular Normal Cell Nutrient Pathway interactions Phosphorylation Phosphotransferases Play Polyubiquitination Process Property Proteins Publishing Regulation Research Role Sampling Signal Pathway Signal Transduction Site Source Stress TRAF6 gene Testing Therapeutic Translating Xenograft procedure base cancer cell cell growth coping design detection of nutrient in vivo innovation mouse model neoplastic cell new therapeutic target novel potential biomarker prostate carcinogenesis research study response sensor therapeutic target transmission process tumor progression tumorigenesis

项目摘要

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.

描述（由申请人提供）：对正常细胞和肿瘤细胞协调生长与营养可用性的机制的研究是细胞生物学的一个基本问题。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，并应对压力。细胞对营养物质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。 mTORC1 是营养传感中的核心激酶，通过调节癌细胞进展的基本过程（例如生长和自噬）。多项研究已经探讨了生长因子、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传导机制尚不清楚。该资助申请基于我们最近发表的研究结果，证明信号转导接头和自噬底物 p62 是氨基酸激活 mTORC1 的新型关键调节剂。这具有重要意义，因为通过激活该途径，p62 可以调节细胞大小和生长，并成为营养感应和自噬调节（正常体内平衡和肿瘤发生中的所有重要事件）中的关键节点。然而，营养物质调节 mTORC1 的精确机制以及 p62 在此过程中的作用仍有待确定。在这方面，我们的初步数据已确定 MEKK3 是 mTORC1 响应氨基酸的 p62 的新伴侣，并且 p62 被新的氨基酸刺激的 MEKK3 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）以激活 mTORC1（癌症进展中的关键事件）的机制。该应用的具体目标是严格检验以下假设：新的 p62/MEKK3 复合物以及 p62 响应营养物质而磷酸化的能力，是通过激活 mTORC1 导致癌症的一个核心过程。这些目标将通过三个具体目标来实现：1) 确定包含 PB1 的 MEKK3 在 p62 调节的 mTORC1 激活中的作用和作用机制； 2）确定p62磷酸化作为营养传感器的作用； 3) 确定新型 p62-MEKK3 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显着影响的概念性进展，这无疑将有助于设计新的癌症治疗靶点。