Novel molecular signaling platform regulating receptor activation and cell function

调节受体激活和细胞功能的新型分子信号平台

• 批准号: RGPIN-2015-05301
• 负责人: Szewczuk, Myron
• 金额: $ 2.19万
• 依托单位: Queen's University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=666339
• 关键词: Novel; molecular; signaling; platform; regulating

Molecular-targeted G-protein-coupled receptor (GPCR) signaling in human disease has become an important area to scientific and medical professionals. I am studying GPCR signaling because my research program has discovered an entirely new GPCR signaling platform. The interactions between GPCRs with their large number of different G-protein subunits and glycosylated receptors involved in all cells of our body are quite diverse. A vast array of stimuli is capable of eliciting conformational changes in these receptors. They are activated by many ligands, both internal within the body, such as hormones and neurotransmitters, and external light, odorants, and others. One GPCR is capable of initiating multifunctional signaling which may potentiate an amplification of the response produced by separate circumstantial signals within the cell. This cross-talk among different GPCR transduction signals is a focus of intense research in the world. My HQPs and I have uncovered the invisible link connecting ligand-binding and receptor activation to a novel GPCR-signaling platform. This molecular organizational GPCR-signaling platform potentiates Neu1 sialidase and matrix metalloproteinase-9 (MMP-9) enzyme cross-talk on growth factor and pathogen-sensing TOLL-like receptors (TLRs) to facilitate receptor association and cellular signaling. The process involves ligand binding to receptors to initiate a conformational change to potentiate GPCR-signaling and MMP-9 activation to induce Neu1. Activated Neu1 specifically hydrolyzes a-2,3-sialyl residues on receptors, the structural perturbation of which triggers dimeric receptor complex formation and subsequent activation. Collectively, this evidence supports a new role for Neu1 and MMP9 enzymes in the activation of glycosylated receptors through yet an undefined mechanism(s). The long term objective is to increase our comprehension at the molecular and genetic levels of the new role for the Neu1-MMP9 crosstalk in alliance with a functional GPCR-signaling complex in controlling receptor activation. We are convinced that our study will provide the first demonstration for this new GPCR signaling platform as a potential signal transducing mechanism for receptors in cellular responses to stimuli. Since several cell-expressed GPCRs have been identified and targeted with therapeutic intent in human diseases involving infectious disease to cancer, studies about the key players potentiating GPCR-signaling to activate MMP-9 and Neu1 would radically redefine the current dogma(s) governing the mechanism of the cross talk between GPCR and cellular responses to stimuli. Targeting the molecular GPCR-signaling platform tethered to growth factor and pathogen-sensing receptors may provide important biological approaches to disease-intervention strategies and to benefit Canadians.

分子靶向G蛋白偶联受体(GPCR)在人类疾病中的信号转导已成为科学和医学工作者关注的重要领域。我之所以研究GPCR信号，是因为我的研究项目发现了一个全新的GPCR信号平台。GPCRs与其大量不同的G蛋白亚基和糖基化受体之间的相互作用在我们身体的所有细胞中都是相当不同的。大量的刺激能够引起这些受体的构象变化。它们被许多配体激活，既有体内的激素和神经递质，也有外部光线、气味等。一个GPCR能够启动多功能信号，这可能会增强细胞内独立的环境信号产生的反应的放大。不同GPCR信号转导信号之间的相互作用是目前国际上研究的热点。我和我的HQP发现了连接配体结合和受体激活与一个新的GPCR信号平台的看不见的联系。这个分子组织的GPCR信号平台增强了Neu1唾液酸酶和基质金属蛋白酶-9(MMP9)在生长因子和病原体敏感的Toll样受体(TLRs)上的相互作用，以促进受体关联和细胞信号传递。这个过程包括配体与受体结合，启动构象变化，加强GPCR信号转导，并激活基质金属蛋白酶-9，以诱导Neu1。激活的Neu1特异性地水解受体上的a-2，3-唾液酸基残基，其结构扰动触发二聚体受体复合体的形成和随后的激活。总的来说，这一证据支持Neu1和MMP9酶通过一种尚未明确的机制在糖基化受体的激活中发挥新的作用(S)。长期的目标是增加我们在分子和遗传水平上对Neu1-MMP9串扰与功能GPCR信号复合体在控制受体激活中的新作用的理解。我们相信，我们的研究将为这个新的GPCR信号平台作为一种潜在的信号转导机制在细胞对刺激的反应中的受体提供第一个示范。由于一些细胞表达的GPCRs已经被发现并被用于人类疾病的治疗意图，关于增强GPCRs信号以激活MMP9和Neu1的关键角色的研究将从根本上重新定义目前支配GPCRs和细胞对刺激的反应之间的串扰机制的教条(S)。针对与生长因子和病原体感应受体捆绑在一起的分子GPCR信号平台，可能为疾病干预战略提供重要的生物学途径，并使加拿大人受益。