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Discrimination between phosphotyrosine-mediated signaling properties of conventional and neuronal Shc adapter molecules

Oncogene volume 21, pages 22–31 (2002)Cite this article

Abstract

The phosphotyrosine (pTyr) adapter Shc/ShcA is a major connector in various tyrosine kinase signalings following a variety of stimulation such as growth factor/neurotrophin, as well as in those following calcium influx and integrin activation. As in other tissues, Shc has been implicated in neuronal signalings; however, recent evidence suggests that N-Shc/ShcC and Sck/ShcB would take over most of the roles of Shc in mature central neurons, and switching phenomena between Shc and N-Shc expression were observed in several neuronal paradigms. Little is, however, known as to the signal-output differences between Shc and N-Shc. Here we determined the efficacy of Shc and N-Shc toward Erk activation in NGF-treated PC12 cells, and found that N-Shc transduced Grb2/Sos/Ras-dependent Erk activation less efficiently than Shc. This was mainly because N-Shc has only one high-affinity Grb2-binding site, whereas Shc has two such sites. Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo. These results indicate that N-Shc has specific features of signal-output, and further suggest that the switching between Shc and N-Shc during neural development and regeneration would lead to differentiation of downstream signalings.

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Acknowledgements

We thank Akiko Nakai, Sachiyo Mimaki, Itsuko Nakano and Yumiko Kadokawa for technical assistance, Chris Marshall and Michiyuki Matsuda for providing EXV3ERK2–Myc and pCAGGS–CrkI, respectively and Hiroshi Morii and Masahiro Sato for comments on the manuscript. This work was supported by a grant from CREST, JST and also, in part, by Strategic Promotion System for Brain Science from STA and Funds for Comprehensive Research on Aging and Health from the Ministry of Health, Labor and Welfare to N Mori.

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Authors and Affiliations

  1. Department of Molecular Genetics, National Institute for Longevity Sciences, Oobu, 474-8522, Aichi, Japan

    Takeshi Nakamura & Nozomu Mori

  2. Program of Protecting the Brain, CREST, JST, Oobu, 474-8522, Aichi, Japan

    Takeshi Nakamura & Nozomu Mori

  3. Biomedical R&D Department, Sumitomo Electric Industries, Sakae-ku, 244-8588, Yokohama, Japan

    Takeshi Nakamura & Misako Komiya

  4. Department of Genetics, The Institute of Medical Science, University of Tokyo, Shirokanedai, 108-0071, Minato-ku, Tokyo, Japan

    Noriko Gotoh & Masabumi Shibuya

  5. Takarazuka Research Institute, Novartis, 665-8666, Miyuki-cho, Takarazuka, Japan

    Shinichi Koizumi

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  1. Takeshi Nakamura
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Correspondence to Nozomu Mori.

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Nakamura, T., Komiya, M., Gotoh, N. et al. Discrimination between phosphotyrosine-mediated signaling properties of conventional and neuronal Shc adapter molecules. Oncogene 21, 22–31 (2002). https://doi.org/10.1038/sj.onc.1205019

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