Nakamura T, Sanokawa R, Sasaki Y, Ayusawa D, Oishi M, Mori N
Biomedical R&D Department, Sumitomo Electric Industries, Yokohama, Japan.
Oncogene. 1996 Sep 19;13(6):1111-21.
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.
Shc通过与活化受体的磷酸酪氨酸残基特异性结合，参与多种生长因子和细胞因子受体信号传导。在神经元细胞如PC12中，已表明在用神经生长因子（NGF）刺激Trk受体后，Shc参与Ras依赖性丝裂原活化蛋白激酶（MAP激酶）的激活。虽然Shc作为衔接分子在信号转导中的普遍作用在神经元和非神经元细胞及组织中都在增加，但Shc在脑中的表达水平却出奇地低。我们在此证明了Shc家族神经特异性成员的分离。这种新蛋白名为N-Shc（神经元Shc），含有两个潜在的磷酸酪氨酸结合结构域，即PTB和SH2，且仅在脑中表达；而Shc存在于所有其他非神经元组织中。与Shc一样，N-Shc可结合活化的表皮生长因子（EGF）受体，发生酪氨酸磷酸化，并在EGF刺激后与Grb2衔接蛋白形成复合物。此外，在用脑源性神经营养因子（BDNF，脑中最丰富的神经营养因子）刺激后，N-Shc可结合活化的TrkB受体。这些数据表明，在中枢神经系统中，是N-Shc而非Shc介导神经营养因子和其他神经元信号传导。
