ShcB and ShcC Activation by the Trk Family of Receptor Tyrosine Kinases

Activation of the neurotrophin Trk receptors is a key process in the survival and development of the nervous system. The signaling adapters ShcB and ShcC, but not ShcA, are thought to be the primary Shc adaptor proteins in neurons as both are highly expressed in both the developing and adult nervous system. Although a previous study suggested that ShcB and ShcC do not strongly interact with the Trk receptors (1), we find that ShcB and ShcC bind the Trk receptors in a phosphotyrosine-dependent manner via their N-terminal phosphotyrosine binding domain at Tyr499 (TrkA) and Tyr515 (TrkB), they are tyrosine-phosphorylated in response to neurotrophin stimulation, and they enhance the activation of mitogen-activated protein kinase in Trk-expressing cells. Moreover, neurotrophin treatment of primary cortical neurons stimulates ShcB/ShcC-Trk interaction and the tyrosine phosphorylation of ShcB/ShcC, indicating that they are bona fide targets of the Trk receptors in vivo. Interestingly, two proteins (pp60 and pp75) co-immunoprecipitate with ShcB and ShcC in response to neurotrophin stimulation in primary cortical neurons, suggesting a potential role of these unknown targets in neurotrophin signaling. Collectively, these results demonstrate that ShcB and ShcC, and their co-immunoprecipitating proteins, are activated by the Trk receptors in primary neurons.