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Domain-specific function of ShcC docking protein in neuroblastoma cells

Oncogene volume 24, pages 3206–3215 (2005)Cite this article

Abstract

ShcC is a family member of the Shc docking proteins that possess two different phosphotyrosine-binding motifs and conduct signals as Grb2-binding substrates of various receptor tyrosine kinases. We have recently shown that some neuroblastoma cell lines, such as NB-39-nu cells, express a protein complex of hyperphosphorylated ShcC and anaplastic lymphoma kinase (ALK), which is self-activated by gene amplification. Here, we demonstrate that the expression of a mutant ShcC lacking Grb2-binding sites, 3YF-ShcC, significantly impaired the survival, differentiation and motility of NB-39-nu cells by blocking the ERK and Akt pathways. On the other hand, cells overexpressing ShcC or 3YF-ShcC, but not a mutant ShcC that lacks SH2, showed decreased anchorage independency and in vivo tumorigenicity, suggesting a novel ShcC-specific suppressive effect through its SH2 domain on cell transformation. Notably, overexpression of ShcC suppressed the sustained phosphorylation of Src family kinase after cell detachment, which might be independent of phosphorylation of Grb2-binding site. It was indicated that the Src/Fyn-Cas pathway is modulated as a target of these suppressive effects by ShcC. Reciprocal change of ShcC expression and phosphorylation observed in malignant neuroblastoma cell lines might be explained by these phosphotyrosine-dependent and -independent functions of ShcC.

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Acknowledgements

This study was supported by the Program for Promotion of Fundamental Studies in Health Sciences of Organization for Pharmaceutical Safety and Research of Japan, and was also supported by a grant from SBS, Inc. Izumi Miyake is the recipient of Research Resident Fellowships from the Japan Health Sciences Foundation.

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Authors and Affiliations

  1. Growth Factor Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Izumi Miyake, Yuko Hakomori & Ryuichi Sakai

  2. Department of Pediatrics, Kitasato University School of Medicine, 1-15-1 Kitasato, Sagamihara-shi, Kanagawa, 228-8555, Japan

    Izumi Miyake, Yoko Misu, Hisaya Nakadate & Nobuo Matsuura

  3. Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Michiie Sakamoto

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  1. Izumi Miyake
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  2. Yuko Hakomori
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Correspondence to Ryuichi Sakai.

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Miyake, I., Hakomori, Y., Misu, Y. et al. Domain-specific function of ShcC docking protein in neuroblastoma cells. Oncogene 24, 3206–3215 (2005). https://doi.org/10.1038/sj.onc.1208523

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