Abstract
The membrane-linked docking protein SNT-2/FRS2β/FRS3 becomes tyrosine phosphorylated in response to fibroblast growth factors (FGFs) and neurotrophins and serves as a platform for recruitment of multiple signaling proteins, including Grb2 and Shp2, to FGF receptors or neurotrophin receptors. We previously reported that SNT-2 is not tyrosine phosphorylated significantly in response to epidermal growth factor (EGF) but that it inhibits ERK activation via EGF stimulation by forming a complex with ERK2. In the present report, we show that expression of SNT-2 suppressed EGF-induced cell transformation and proliferation, and expression level of SNT-2 is downregulated in cancer. The activities of the major signaling molecules in EGF receptor (EGFR) signal transduction pathways, including autophosphorylation of EGFR, were attenuated in cells expressing SNT-2 but not in cells expressing SNT-2 mutants lacking the ERK2-binding domain. Furthermore, SNT-2 constitutively bound to EGFR through the phosphotyrosine binding (PTB) domain both with and without EGF stimulation. Treatment of cells with MEK inhibitor U0126 partially restored the phosphorylation levels of MEK and EGFR in cells expressing SNT-2. On the basis of these findings, we propose a novel mechanism of negative control of EGFR tyrosine kinase activity with SNT-2 by recruiting ERK2, which is the site of negative-feedback loop from ERK, ultimately leading to inhibition of EGF-induced cell transformation and proliferation.
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Acknowledgements
We are grateful to Dr Toshio Kitamura for valuable reagents for retrovirus expression system and Ms Takako Horii for technical assistance. We thank Drs Jun Yokota and Masachika Tani for valuable cell lines and discussion. This work was supported by Grants-in-Aid for Special Project Research on Stem Cells (17045008) to NG and on Cancer-Bioscience (17013025) to NG and (17014020) to MS from the Ministry of Education, Science, Sports and Culture of Japan, by The Mochida Memorial Foundation for Medical and Pharmaceutical Research to NG, by NOVARTIS Foundation (Japan) for the Promotion of Science to NG, by Grants-in-Aid for the program ‘Research for the Future’ of the Japan Society for the Promotion of Science and for the program ‘Promotion of Fundamental Research in Health Sciences’ from the Organization for Pharmaceutical Safety and Research (OPSR) to MS, and by Japan Society for the Promotion of Science (16390520) to NT. LH is a recipient of Honjo International Scholarship Foundation.
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Huang, L., Watanabe, M., Chikamori, M. et al. Unique role of SNT-2/FRS2β/FRS3 docking/adaptor protein for negative regulation in EGF receptor tyrosine kinase signaling pathways. Oncogene 25, 6457–6466 (2006). https://doi.org/10.1038/sj.onc.1209656
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DOI: https://doi.org/10.1038/sj.onc.1209656
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