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

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


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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


Kurokawa View author publications You can also search for this author inPubMed Google Scholar * Toshihide Iwashita View author publications You can also search for this author inPubMed 


Google Scholar * Hideki Murakami View author publications You can also search for this author inPubMed Google Scholar * Hironori Hayashi View author publications You can also search for this


author inPubMed Google Scholar * Kumi Kawai View author publications You can also search for this author inPubMed Google Scholar * Masahide Takahashi View author publications You can also


search for this author inPubMed Google Scholar RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 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