Signalling mechanisms of the ShcD adaptor protein

ShcD 接头蛋白的信号传导机制

• 批准号: RGPIN-2017-05197
• 负责人: Jones, Nina
• 金额: $ 3.64万
• 依托单位: University of Guelph
• 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=654819
• 关键词: Signalling; mechanisms; ShcD; adaptor; protein

Signal transduction is a central process in multicellular organisms whereby the mutual exchange of informational cues directs biological responses such as growth, migration, differentiation and survival. Cells have evolved a tremendous ability to activate distinct biochemical pathways, and the Shc family of intracellular adaptor proteins provides a unique opportunity to investigate the questions of selectivity and specificity. These proteins function to relay phosphotyrosine-based signals from activated cell surface receptors (such as EGFR, TrkA/B and Ret) to various effector proteins including Erk/MAPK, and they play critical roles in development. Intriguingly, the Shc family has increased in complexity from one gene in flies to several in mammals, and we have characterized a fourth mammalian homolog, ShcD. We have found that this adaptor diverges from canonical Shc signaling in its ability to autoactivate the EGFR and alter its intracellular trafficking, removing it from the cell surface such that it can no longer respond to ligand cues. ShcD further suppresses activation of Erk downstream of EGFR, TrkA/B and Ret, unlike ShcA-C. To better understand the physiological function of ShcD, we have recently generated ShcD knockout (KO) mice, and preliminary analysis indicates that aged ShcD KO mice exhibit reduced olfactory bulb (OB) size and progressive defects in olfaction that have not been reported following loss of other Shc proteins. The OB is a site of continuous remodeling associated with lifelong neuronal turnover, and our findings raise the exciting possibility that ShcD might be uniquely involved in adult neurogenesis. Herein, we will capitalize on the novel genetic and molecular resources that we have amassed to further explore the olfactory defect in ShcD KO mice, and use complementary cell systems and biochemical approaches to classify the processes and pathways that are engaged by ShcD. The overall goal of this study is to dissect the Shc protein signaling paradigm and define the select and specific role of ShcD in neural signaling biology. As olfactory deficits are associated with neurodegenerative disorders that impact Canadians, our findings may also provide mechanistic insight to explain how perturbations in cellular communication can lead to altered cell function.*****************

信号转导是多细胞生物体中的一个中心过程，其中信息线索的相互交换指导生物反应，如生长，迁移，分化和存活。细胞已经进化出激活不同生化途径的巨大能力，并且细胞内衔接蛋白的Shc家族提供了研究选择性和特异性问题的独特机会。这些蛋白质的功能是将来自激活的细胞表面受体（例如EGFR、TrkA/B和Ret）的基于磷酸酪氨酸的信号传递给包括Erk/MAPK在内的各种效应蛋白，并且它们在发育中发挥关键作用。有趣的是，Shc家族的复杂性从果蝇中的一个基因增加到哺乳动物中的几个基因，我们已经确定了第四个哺乳动物同源物，ShcD。我们已经发现，这种衔接子在其自激活EGFR并改变其细胞内运输的能力方面与典型的Shc信号传导不同，将其从细胞表面移除，使得其不再对配体提示做出反应。与ShcA-C不同，ShcD进一步抑制EGFR、TrkA/B和Ret下游Erk的活化。为了更好地了解ShcD的生理功能，我们最近产生了ShcD敲除（KO）小鼠，初步分析表明，老年ShcD KO小鼠表现出嗅球（OB）大小减少和嗅觉进行性缺陷，这些缺陷在其他Shc蛋白丢失后尚未报道。OB是一个与终身神经元更新相关的持续重塑的位点，我们的研究结果提出了令人兴奋的可能性，即ShcD可能是唯一参与成人神经发生的。在此，我们将利用我们积累的新的遗传和分子资源，进一步探索ShcD KO小鼠的嗅觉缺陷，并使用互补细胞系统和生物化学方法对ShcD参与的过程和途径进行分类。本研究的总体目标是剖析Shc蛋白信号转导模式，并确定ShcD在神经信号生物学中的选择和特异性作用。由于嗅觉缺陷与影响加拿大人的神经退行性疾病有关，我们的研究结果也可能提供机制上的见解，以解释细胞通讯的扰动如何导致细胞功能的改变。