Novel molecular signaling platform regulating receptor activation and cell function

分子靶向g蛋白偶联受体（GPCR）信号在人类疾病中的应用已成为科学界和医学界关注的一个重要领域。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。gpcr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非常多样化的。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，包括身体内部的配体，如激素和神经递质，以及外部的光，气味剂等。一个GPCR能够启动多功能信号，这可能会增强细胞内单独环境信号产生的反应的放大。这种不同GPCR转导信号之间的串扰是目前国际上研究的热点。我的HQPs和我已经发现了连接配体结合和受体激活与一种新的gpcr信号传导平台的隐形联系。这个分子组织gpcr信号传导平台增强了Neu1唾液酸酶和基质金属蛋白酶-9 （MMP-9）酶在生长因子和病原体感应toll样受体（TLRs）上的串扰，促进了受体的结合和细胞信号传导。该过程包括配体与受体结合，启动构象变化，增强gpcr信号传导和MMP-9激活，诱导Neu1。活化的Neu1特异性水解受体上的a-2,3-唾液酸残基，其结构扰动触发二聚体受体复合物的形成和随后的激活。总的来说，这些证据支持Neu1和MMP9酶在糖基化受体激活中的新作用，其机制尚未明确。长期目标是增加我们在分子和遗传水平上对Neu1-MMP9串扰与功能性gpcr信号复合物在控制受体激活中的新作用的理解。我们相信，我们的研究将首次证明这种新的GPCR信号传导平台是细胞对刺激反应中受体的潜在信号转导机制。由于几种细胞表达的GPCR已经被鉴定出来，并在包括感染性疾病和癌症在内的人类疾病中具有治疗目的，因此对增强GPCR信号以激活MMP-9和Neu1的关键参与者的研究将从根本上重新定义当前控制GPCR与细胞对刺激反应之间串扰机制的教条。靶向与生长因子和病原体感应受体相连的分子gpcr信号平台可能为疾病干预策略提供重要的生物学途径，并使加拿大人受益。

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.