Signalling mechanisms of the ShcD adaptor protein

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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.