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J Biol Chem, Vol. 273, Issue 12, 6960-6967, March 20, 1998
,, and
**
From the 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.
Biomedical Research and Development
Department, Sumitomo Electric Industries, Sakae-ku, Yokohama 244, the
¶ Inheritance and Variation Group, PRESTO, Science and Technology
Corporation of Japan, Keihanna Plaza, Seika-cho, Kyoto 619-02, and the
Program of Protecting Brain, CREST, Science and Technology
Corporation of Japan and the ** Department of Molecular Genetic
Research, National Institute for Longevity Science, Oobu,
Aichi 474, Japan
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