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Neu-mediated phosphorylation of protein tyrosine phosphatase epsilon is critical for activation of Src in mammary tumor cells

Oncogene volume 26, pages 7028–7037 (2007)Cite this article

Abstract

The receptor-type protein tyrosine phosphatase epsilon (RPTPɛ) activates c-Src in mammary tumor cells induced in vivo by Neu. Tumor cells lacking RPTPɛ exhibit reduced c-Src activity, appear less transformed morphologically and proliferate slower in vitro and in vivo. Expression of Src rescues most of these phenotypes, indicating that c-Src activity is important for maintaining the transformed phenotype. However, the molecular mechanisms that control activation of c-Src by RPTPɛ are unknown. We show that Neu induces phosphorylation of RPTPɛ exclusively at its C-terminal Y695, and that this phosphorylation is required for activation of c-Src by RPTPɛ. Phosphorylation of RPTPɛ does not affect its activity toward another substrate, the voltage-gated potassium channel Kv2.1, suggesting that phosphorylation directs RPTPɛ activity toward c-Src. Phosphorylation of RPTPɛ reduces its dimerization at the cell membrane, although this does not affect its activity significantly. RPTPɛ is subject to strong auto- and trans-dephosphorylation, suggesting that dephosphorylation limits the activation of c-Src downstream of Neu. We conclude that an Neu-RPTPɛ-Src signaling pathway exists in mammary tumor cells, in which phosphorylation of RPTPɛ by Neu directs RPTPɛ to activate c-Src. Reversible phosphorylation of RPTPɛ at Y695 may thus function as a ‘molecular switch’, which affects the substrate specificity of the phosphatase.

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Acknowledgements

We thank colleagues mentioned in the text for gifts of valuable reagents. This study was supported by the Israel Cancer Research Fund, the Minerva Foundation (Munich, Germany), and the Women's Health Research Center at the Weizmann Institute.

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  1. Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, Israel

    D Berman-Golan & A Elson

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  1. D Berman-Golan
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  2. A Elson
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Correspondence to A Elson.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Berman-Golan, D., Elson, A. Neu-mediated phosphorylation of protein tyrosine phosphatase epsilon is critical for activation of Src in mammary tumor cells. Oncogene 26, 7028–7037 (2007). https://doi.org/10.1038/sj.onc.1210505

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