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Identification of SNT/FRS2 docking site on RET receptor tyrosine kinase and its role for signal transduction

Oncogene volume 20, pages 1929–1938 (2001)Cite this article

Abstract

SNT/FRS2 is a lipid anchored docking protein that contains an amino-terminal myristylation signal, followed by a phosphotyrosine-binding (PTB) domain and a carboxy-terminal region with multiple tyrosine residues. Here we show that the SNT/FRS2 PTB domain binds to RET receptor tyrosine kinase activated by glial cell line-derived neurotrophic factor (GDNF) or multiple endocrine neoplasia (MEN) 2 mutations. Analyses by site directed-mutagenesis revealed that it binds to tyrosine 1062 in RET that is also known to be a binding site for the SHC adaptor protein. Whereas SHC bound to RET was associated with GRB2 and GAB1 proteins, SNT/FRS2 was associated with GRB2 only, suggesting that SNT/FRS2 is involved mainly in the activation of the RAS/mitogen activated protein kinase (MAPK) pathway but not the phosphatidylinositol 3-kinase (PI3-K)/AKT pathway. In addition, phosphorylated SNT/FRS2 appeared to directly complex with SHP-2 tyrosine phosphatase. These results suggest that tyrosine 1062 in RET provides a site for the interaction of multiple signaling molecules and that the balance of SHC and SNT/FRS2 binding may affect the nature of the intracellular signaling for cell proliferation, differentiation and survival induced by activated RET.

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Acknowledgements

We are grateful to K Imaizumi and M Kozuka for their technical assistance. This work was supported in part by a grant-in-aid for COE (Center of Excellence) research from the Ministry of Education, Science, Sports and Culture of Japan.

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

    Kei Kurokawa, Toshihide Iwashita, Hideki Murakami, Hironori Hayashi, Kumi Kawai & Masahide Takahashi

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  1. Kei Kurokawa
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Kurokawa, K., Iwashita, T., Murakami, H. et al. Identification of SNT/FRS2 docking site on RET receptor tyrosine kinase and its role for signal transduction. Oncogene 20, 1929–1938 (2001). https://doi.org/10.1038/sj.onc.1204290

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