N-Shc and Sck, two neuronally expressed Shc adapter homologs. Their differential regional expression in the brain and roles in neurotrophin and Src signaling.
The Shc adapter protein is ubiquitously expressed and has been implicated in phosphotyrosine signalings following a variety of extracellular stimulation, e.g. growth factor stimulation, Ca2+ elevation, and G-protein-coupled receptor stimulation. In neuronal cells such as PC12, Shc was demonstrated to be involved in vitro in Ras-dependent mitogen-activated protein kinase activation following nerve growth factor stimulation and Ca2+ entry. However, Shc mRNA was hardly detectable in the brain, and therefore, Shc is unlikely to participate in phosphotyrosine signaling in the central nervous system. Two recently isolated Shc homologs, N-Shc and Sck, have been shown to be expressed in the brain and are expected to function as neuronal adapters instead of Shc. In this study, the neuronal distribution and function of these novel Shc members were investigated. In human and rat central nervous systems, the expression profiles of N-Shc and Sck mRNAs considerably overlapped, although some distinct localization between them was observed: in the adult rat brain, the level of N-Shc mRNA was the highest in the thalamus, whereas that of Sck mRNA was the highest in the hippocampus. In the peripheral nervous system, transcripts of Shc and Sck, but not of N-Shc, were detected. Immunoprecipitation experiments demonstrated functional differences between N-Shc and Sck: (i) N-Shc was a higher affinity adapter molecule than Sck in nerve growth factor and brain-derived neurotrophic factor signaling; and (ii) N-Shc, but not Sck, was efficiently phosphorylated by activated Src tyrosine kinase, whereas Sck, but not N-Shc, formed a complex with pp135, a protein highly phosphorylated by v-Src. These results suggest that neurally expressed N-Shc and Sck may have distinct roles in neuronal signaling in the brain.
Nakamura
T
T
Biomedical Research and Development Department, Sumitomo Electric Industries, Sakae-ku, Yokohama 244, Japan.
Muraoka
S
S
Sanokawa
R
R
Mori
N
N
D016475:3T3 Cells; D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D003001:Cloning, Molecular; D018076:DNA, Complementary; D004815:Epidermal Growth Factor / Q000378:metabolism; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D011485:Protein Binding; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D020801:Receptor, Ciliary Neurotrophic Factor; D020917:Receptor, trkA; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D000071426:Src Homology 2 Domain-Containing, Transforming Protein 2; D019061:src-Family Kinases / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D018076:DNA, Complementary; D011506:Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D020801:Receptor, Ciliary Neurotrophic Factor; D017475:Receptors, Nerve Growth Factor; C528024:SHC1 protein, human; C099021:SHC2 protein, human; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; C528035:Shc1 protein, rat; C486295:Shc2 protein, mouse; C486296:Shc2 protein, rat; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D000071426:Src Homology 2 Domain-Containing, Transforming Protein 2; D004815:Epidermal Growth Factor; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA; D019061:src-Family Kinases