Chemical Genetic Analysis of RAS Signaling

RAS 信号转导的化学遗传学分析

• 批准号: 10589943
• 负责人: Dustin J Maly
• 金额: $ 32.78万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589943
• 关键词: Address; Affect; Behavior; Behavior Control; Binding; Biology; Cancer cell line; Cell physiology; Cells; Chemicals; Clinical; Complex; Development; Dimerization; Dose; Environment; Enzymes; Eukaryota; Feedback; GTP Binding; Generations; Guanosine Triphosphate Phosphohydrolases; Investigation; KRAS oncogenesis; Location; MEKs; Malignant Neoplasms; Mammalian Cell; Mediating; Methods; Molecular; Oncogenic; Output; Pathway interactions; Permeability; Phosphotransferases; Play; Process; Proliferating; Protein Isoforms; Proteins; Proteomics; RAS genes; RAS inhibition; Ras Inhibitor; Resistance; Role; Signal Pathway; Signal Transduction; System; T-Cell Development; Technology; Time; Work; chemical genetics; dimer; genetic analysis; inhibitor; inhibitor therapy; insight; interest; kinase inhibitor; migration; mutant; novel; phosphoproteomics; recruit; response; small molecule; spatiotemporal; technology platform; tool; trafficking; transcriptomics

Abstract The GTPase RAS functions as a molecular “on/off” switch, existing both in GDP-bound (inactive) and GTP- bound forms (active). Despite functioning as a simple binary switch, RAS is capable of directing complex and diverse cellular processes, including proliferation, migration, survival, and T-cell development. Recent work suggests that the ability of RAS to play complex, often conflicting roles in diverse processes results from differences in cellular context and and/or subcellular localization of its signaling. We have developed a novel chemical genetic tool–called Chemically-Inducible Activator of RAS (CIAR)–to study the dynamics of the signaling networks that are mediated by RAS activity. CIAR allows rapid and dose-dependent activation of RAS signaling with a cell permeable small molecule. With CIAR, we propose to use targeted, quantitative phosphoproteomics and transcriptomics to study the fundamental dynamic behavior of RAS-driven signaling. Subcellularly-localized versions of CIAR will also be used to determine the effects of localized RAS activation on the dynamics of RAS-mediated signaling. Finally, we will explore positive and negative feedback within RAS-driven signaling pathways by selectively enhancing or inhibiting downstream signaling components.

摘要