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N-Shc: a neural-specific adapter molecule that mediates signaling from neurotrophin/Trk to Ras/MAPK pathway
T Nakamura1, R Sanokawa, Y Sasaki
1Biomedical R&D Department, Sumitomo Electric Industries, Yokohama, Japan.
Abstract:
Shc has been implicated in a variety of growth factor- and cytokine receptor-signaling through its specific binding to phosphotyrosine residues of the activated receptors. In neuronal cells, such as PC12, Shc has been shown to be involved in Ras-dependent MAP kinase activation following Trk receptor stimulation with NGF. While the ubiquitous role of Shc as an adaptor molecule in signal transduction is increasing in both neuronal and non-neuronal cells and tissues, the expression level of Shc is surprisingly low in the brain. We demonstrated here the isolation of a neural-specific member of the Shc family. This novel protein, named N-Shc (neuronal Shc), contains two potential phosphotyrosine-binding domains, PTB and SH2, and is expressed exclusively in the brain; whereas Shc is present in all other non-neuronal tissues. As in Shc, N-Shc can bind activated EGF receptor, become tyrosine phosphorylated, and form a complex with Grb2 adapter protein following EGF stimulation. Furthermore, N-Shc can bind activated TrkB receptor following the stimulation with brain-derived neurotrophic factor (BDNF), which is the most abundant neurotrophin in the brain. These data suggest that N-Shc, rather than Shc, mediates neurotrophin and other neuronal signalings in the central nervous system.
Insights
Researchers discovered a new protein, neuronal Shc (N-Shc), exclusively in the brain. N-Shc plays a key role in neuronal signaling pathways, mediating neurotrophin effects in the central nervous system.
Area of Science:
- Neuroscience
- Molecular Biology
- Signal Transduction
Background:
- Shc proteins act as adaptors in growth factor and cytokine receptor signaling.
- Shc is involved in Ras-MAP kinase activation in neuronal cells but has low expression in the brain.
Purpose of the Study:
- To identify and characterize a neural-specific Shc family member.
- To investigate the role of this novel protein in neuronal signaling.
Main Methods:
- Isolation and characterization of the novel N-Shc protein.
- Assays for receptor binding, tyrosine phosphorylation, and protein complex formation.
- Analysis of N-Shc expression in brain tissue.
Main Results:
- A neural-specific Shc family member, N-Shc, was identified with PTB and SH2 domains.
- N-Shc is expressed exclusively in the brain, unlike the ubiquitous Shc.
- N-Shc binds activated EGF and TrkB receptors, becomes phosphorylated, and complexes with Grb2 upon stimulation.
- N-Shc binds to brain-derived neurotrophic factor (BDNF) activated TrkB receptors.
Conclusions:
- N-Shc is the primary mediator of neurotrophin and other neuronal signaling in the central nervous system.
- N-Shc likely plays a more significant role than Shc in brain signal transduction.