N-Shc: a neural-specific adapter molecule that mediates signaling from neurotrophin/Trk to Ras/MAPK pathway.
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.
Nakamura
T
T
Biomedical R&D Department, Sumitomo Electric Industries, Yokohama, Japan.
Sanokawa
R
R
Sasaki
Y
Y
Ayusawa
D
D
Oishi
M
M
Mori
N
N
D016475:3T3 Cells; D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000502:physiology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism / Q000502:physiology*; D019556:COS Cells; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D018076:DNA, Complementary / Q000235:genetics / Q000302:isolation & purification; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000502:physiology; D066246:ErbB Receptors / Q000378:metabolism / Q000502:physiology; D051380:GRB2 Adaptor Protein; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D010766:Phosphorylation; D011506:Proteins / Q000378:metabolism / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism / Q000502:physiology*; D020813:Receptor, trkB; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism / Q000502:physiology*; D012680:Sensitivity and Specificity; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism / Q000502:physiology*; D018909:src Homology Domains / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D019208:Brain-Derived Neurotrophic Factor; D018076:DNA, Complementary; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; C495949:Grb2 protein, mouse; D011506:Proteins; D017475:Receptors, Nerve Growth Factor; D014443:Tyrosine; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D020813:Receptor, trkB; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D018631:ras Proteins