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Characterization of intracellular signals via tyrosine 1062 in RET activated by glial cell line-derived neurotrophic factor

Oncogene volume 19, pages 4469–4475 (2000)Cite this article

Abstract

Glial cell line derived neurotrophic factor (GDNF) signals through a multicomponent receptor complex consisting of RET receptor tyrosine kinase and a member of GDNF family receptor α (GFRα). Recently, it was shown that tyrosine 1062 in RET represents a binding site for SHC adaptor proteins and is crucial for both RAS/mitogen activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3-K)/AKT signaling pathways. In the present study, we characterized how these two pathways diverge from tyrosine 1062, using human neuroblastoma and primitive neuroectodermal tumor cell lines expressing RET at high levels. In response to GDNF stimulation, SHC bound to GAB1 and GRB2 adaptor proteins as well as RET, and SHC and GAB1 were highly phosphorylated on tyrosine. The complex formation consisting of SHC, GAB1 and GRB2 was almost abolished by replacement of tyrosine 1062 in RET with phenylalanine. Tyrosine-phosphorylated GAB1 was also associated with p85 subunit of PI3-K, resulting in PI3-K and AKT activation, whereas SHC-GRB2-SOS complex was responsible for the RAS/ERK signaling pathway. These results suggested that the RAS and PI3-K pathways activated by GDNF bifurcate mainly through SHC bound to tyrosine 1062 in RET. Furthermore, using luciferase reporter-gene assays, we found that the RAS/ERK and PI3-K signaling pathways are important for activation of CREB and NF-κB in GDNF-treated cells, respectively.

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Acknowledgements

We are grateful to K Imaizumi and M Kozuka for technical assistance. This work was supported in part by grants-in-aid for COE research and scientific research from the Ministry of Education, Science, Sports and Culture of Japan.

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Authors and Affiliations

  1. Department of Pathology, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan

    Hironori Hayashi, Masatoshi Ichihara, Toshihide Iwashita, Hideki Murakami, Yohei Shimono, Kumi Kawai, Kei Kurokawa, Yoshiki Murakumo & Masahide Takahashi

  2. Department of Surgery, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan

    Hironori Hayashi, Tsuneo Imai, Hiroomi Funahashi & Akimasa Nakao

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  1. Hironori Hayashi
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Hayashi, H., Ichihara, M., Iwashita, T. et al. Characterization of intracellular signals via tyrosine 1062 in RET activated by glial cell line-derived neurotrophic factor. Oncogene 19, 4469–4475 (2000). https://doi.org/10.1038/sj.onc.1203799

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