Signalling mechanisms of the ShcD adaptor protein

信号转导是多细胞生物体的一个中心过程，通过信息线索的相互交换来指导生物反应，如生长、迁移、分化和生存。细胞已经进化出了激活不同生化途径的巨大能力，而Shc家族的细胞内适配器蛋白为研究选择性和特异性问题提供了一个独特的机会。这些蛋白的功能是将激活的细胞表面受体(如EGFR、TrkA/B和Ret)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，在发育过程中发挥关键作用。有趣的是，Shc家族的复杂性已经从苍蝇的一个基因增加到哺乳动物的几个基因，我们已经确定了第四个哺乳动物同源基因ShcD的特征。我们发现，这个接头与经典的Shc信号不同，因为它能够自动激活EGFR并改变其在细胞内的运输，将其从细胞表面移除，从而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的激活。为了更好地了解ShcD的生理功能，我们最近培育了ShcD基因敲除(KO)小鼠，初步分析表明，衰老的ShcD KO小鼠表现出嗅球(OB)尺寸减小和进行性嗅觉缺陷，这在其他Shc蛋白丢失后尚未见报道。OB是一个与终生神经元更替相关的持续重塑的部位，我们的发现提出了ShcD可能是唯一参与成人神经发生的令人兴奋的可能性。在这里，我们将利用我们积累的新的遗传和分子资源来进一步探索ShcD KO小鼠的嗅觉缺陷，并使用互补细胞系统和生化方法来对ShcD参与的过程和途径进行分类。这项研究的总体目标是剖析Shc蛋白的信号传递范式，并确定ShcD在神经信号生物学中的选择和特定作用。由于嗅觉缺陷与影响加拿大人的神经退行性疾病有关，我们的发现也可能提供机械方面的见解，解释细胞通讯的干扰如何导致细胞功能改变。

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.