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：
10542413
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 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10542413
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 Phosphorylation Inhibition Phosphotransferases Physiological Physiological Processes Play Process Protein Biosynthesis Protein Inhibition Protein Isoforms Proteins Regulation Research Role Signal Pathway Signal Transduction Sirolimus Stimulus Survival Rate 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.

抽象的雷帕霉素的哺乳动物靶标（MTOR）是一种进化保守的Ser/Thr激酶，可以感觉到多个上游刺激以调节细胞生长，代谢和自噬。 MTOR是多数的关键组成部分蛋白质复合物称为MTOR复合物1（MTORC1）。 MTORC1激活增加在人类中很常见包括癌症，2型糖尿病，代谢疾病和神经退行性的疾病。小分子喜欢目前在诊所中使用了靶标和抑制MTORC1的雷帕霉素，成功有限。那是解密的 MTORC1调控涉及的分子机制对于治疗MTORC1介导的疾病。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酸。相反，对可以直接抑制MTORC1活性的信号通路知之甚少。 G蛋白与GαS蛋白配对的耦合受体（GPCR）通过增加细胞内激活蛋白激酶A（PKA）环状腺苷3'5'单磷酸盐（CAMP）水平。 PKA磷酸化MTORC1组件猛禽和潜在地抑制MTORC1活性。重要的是，GPCR是最大的药物靶标家族，许多家族 FDA已批准化合物来调节GPCR信号。我们的初步数据进一步揭示了机械细节并确定PKA抑制MTORC1涉及的新组件（特定目标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（特定目的） 3）。因此，该提案的总体目标是破译分子机制 PKA抑制MTORC1并调节MTORC1介导的生物学。我们预计拟议的研究将通过PKA对MTORC1调节产生新的见解，并将发现治疗靶标的扰动MTORC1- 介导的疾病。