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Protein tyrosine phosphatase epsilon and Neu-induced mammary tumorigenesis

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Abstract

Aberrant regulation of the phosphorylation of proteins on tyrosine residues is a well-established cause of cancer. Protein tyrosine phosphatases (PTPs) share in the crucial function of maintaining appropriate levels of phosphorylation of cellular proteins, making them potentially key players in regulating the transformation process. The receptor-type tyrosine phosphatase Epsilon (RPTPɛ) participates in supporting the transformed phenotype of mammary tumor cells induced in vivo by the Neu tyrosine kinase. The phosphatase is overexpressed in mammary tumors induced in mice by a Neu transgene and expression of RPTPɛ in mouse mammary glands leads to massive hyperplasia and associated tumorigenesis. Furthermore, cells isolated from mammary tumors induced by Neu in mice genetically lacking RPTPɛ appear less transformed and proliferate less well than corresponding mammary tumor cells isolated from mice expressing the phosphatase. At the molecular level, RPTPɛ dephosphorylates and activates Src and the related kinases Yes and Fyn, and the activities of these kinases are significantly reduced in tumor cells lacking RPTPɛ. Restoring the activities of these kinases reveals that it is only the reduced activity of Src that causes the aberrant morphology and proliferation rate of tumor cells lacking RPTPɛ. RPTPɛ is primed to activate Src, and presumably related kinases, following its phosphorylation by Neu at Y695 within its C-terminus. This event is crucial in enabling RPTPɛ to activate Src, but appears not to affect the activity of RPTPɛ towards unrelated substrates. We conclude that a Neu-RPTPɛ-Src pathway exists in mouse mammary tumor cells, in which Neu phosphorylates RPTPɛ thereby driving the phosphatase to specifically activate Src family kinases and to assist in maintaining the transformed phenotype.

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Abbreviations

Cyt-PTPe:

Non receptor isoform of PTP epsilon

EKO:

PTP epsilon knockout

MMTV:

Mouse Mammary Tumor Virus

PTP:

protein tyrosine phosphatase

RPTPa:

receptor PTP alpha

RPTPe:

receptor isoform of PTP epsilon

WT:

Wild -Type

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Acknowledgements

We gratefully acknowledge support by the Israel Science Foundation, founded by the Israel Academy of Sciences and Humanities; by the United States-Israel Binational Science Foundation; by the Israel Cancer Research Fund; by the US Army Research and Materiel Command; and by 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, 76100, Israel

    Dalia Berman-Golan, Shira Granot-Attas & Ari Elson

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  1. Dalia Berman-Golan
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  2. Shira Granot-Attas
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  3. Ari Elson
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Correspondence to Ari Elson.

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Berman-Golan, D., Granot-Attas, S. & Elson, A. Protein tyrosine phosphatase epsilon and Neu-induced mammary tumorigenesis. Cancer Metastasis Rev 27, 193–203 (2008). https://doi.org/10.1007/s10555-008-9124-0

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  • DOI: https://doi.org/10.1007/s10555-008-9124-0

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