Deciphering the Molecular Mechanisms by which PKA inhibits mTORC1

破译 PKA 抑制 mTORC1 的分子机制

基本信息

批准号：
10365712
负责人：
Jenna L Jewell
金额：
$ 34.44万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10365712
关键词：
5&apos -AMP-activated protein kinase A kinase anchoring protein Aging Agonist Amino Acids Autophagocytosis Binding Biochemical Biological Biological Process Biology Cancer Patient Catabolic Process Catalytic Domain Cell Proliferation Cell physiology Cells Clinic Complex Coupled Couples Cues Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Disease Drug Targeting Event FDA approved FRAP1 gene Family G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs Goals Growth Factor Hormones Human Cell Line Knock-in Mouse Location Malignant Neoplasms Malignant neoplasm of lung Mediating Metabolic Diseases Metabolism Molecular Multiprotein Complexes Mus Nerve Degeneration Non-Insulin-Dependent Diabetes Mellitus Nutrient Obesity Organism Pathway interactions Periodicity Phosphorylation Phosphotransferases Physiological Physiological Processes Play Process Protein Biosynthesis Protein Inhibition Protein Isoforms Protein Kinase Proteins Raptors Regulation Research Role Signal Pathway Signal Transduction Sirolimus Stimulus Survival Rate base cancer type cell growth combat experimental study human disease in vivo insight live cell imaging mouse model new therapeutic target novel protein activation protein complex small molecule success therapeutic target tumor growth

项目摘要

ABSTRACT The mammalian target of rapamycin (mTOR) is an evolutionary conserved Ser/Thr kinase that can sense multiple upstream stimuli to regulate cell growth, metabolism, and autophagy. mTOR is the key component of a multi- protein complex termed mTOR complex 1 (mTORC1). Increased mTORC1 activation is common in human disease including cancer, type 2 diabetes, metabolic disorders, and neurodegeneration. Small molecules like rapamycin that target and inhibit mTORC1, are currently used in the clinic with limited success. Thus, deciphering the molecular mechanisms involved in mTORC1 regulation is crucial in order to treat mTORC1-mediated disease. The majority of research has focused on stimuli that activate mTORC1, like growth factors and amino acids. In contrast, less is known about signaling pathways that can directly inhibit mTORC1 activity. G-protein coupled receptors (GPCRs) paired to Gαs proteins activate Protein Kinase A (PKA) by increasing intracellular cyclic adenosine 3’5’ monophosphate (cAMP) levels. PKA phosphorylates the mTORC1 component Raptor and potently inhibits mTORC1 activity. Importantly, GPCRs are the largest family of drug targets and many compounds have been approved by the FDA to regulate GPCR signaling. Our preliminary data reveals further mechanistic detail and identifies new components involved in mTORC1 inhibition by PKA (Specific Aims 1-2). Moreover, we will determine the role of PKA signaling in mTORC1-mediated biology and disease (Specific Aim 3). Therefore, the overall objective of this proposal is to decipher the molecular mechanisms by which PKA inhibits mTORC1 and regulates mTORC1-mediated biology. We anticipate that the proposed studies will yield new insights into mTORC1 regulation by PKA and will uncover therapeutic targets to perturb mTORC1- mediated disease.

抽象的哺乳动物雷帕霉素靶蛋白 (mTOR) 是一种进化保守的 Ser/Thr 激酶，可以感知多种 mTOR 是调节细胞生长、代谢和自噬的上游刺激的关键组成部分。称为 mTOR 复合物 1 (mTORC1) 的蛋白质复合物在人类中很常见。疾病，包括癌症、2 型糖尿病、代谢紊乱和神经退行性疾病等。靶向并抑制 mTORC1 的雷帕霉素目前在临床中使用，但取得的成功有限。 mTORC1 调节涉及的分子机制对于治疗 mTORC1 介导的疾病至关重要大多数研究都集中在激活 mTORC1 的刺激上，例如生长因子和氨基。相比之下，人们对直接抑制 mTORC1 活性的信号通路知之甚少。与 Gαs 蛋白配对的偶联受体 (GPCR) 通过增加细胞内环腺苷 3'5' 单磷酸 (cAMP) 水平使 mTORC1 成分 Raptor 磷酸化和有效抑制 mTORC1 活性重要的是，GPCR 是最大的药物靶点家族。我们的初步数据已被 FDA 批准用于调节 GPCR 信号传导。机制细节并确定了参与 PKA 抑制 mTORC1 的新成分（具体目标 1-2）。此外，我们将确定 PKA 信号在 mTORC1 介导的生物学和疾病中的作用（具体目标 3）因此，该提案的总体目标是破译其分子机制。 PKA 抑制 mTORC1 并调节 mTORC1 介导的生物学。将产生对 PKA 调节 mTORC1 的新见解，并将发现扰乱 mTORC1 的治疗靶点- 介导的疾病。