Identification of snt/frs2 docking site on ret receptor tyrosine kinase and its role for signal transduction

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. Access through your institution Buy or subscribe

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Download references 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. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * 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 Authors * Kei

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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 Download

citation * Received: 17 November 2000 * Revised: 16 January 2001 * Accepted: 18 January 2001 * Issue Date: 12 April 2001 * DOI: https://doi.org/10.1038/sj.onc.1204290 SHARE THIS ARTICLE

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by the Springer Nature SharedIt content-sharing initiative KEYWORDS * SNT/FRS2 * RET * SHC * GDNF * MEN2