Protein tyrosine phosphatase epsilon and Neu-induced mammary tumorigenesis

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 (RPTPepsilon) 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 RPTPepsilon in mouse mammary glands leads to massive hyperplasia and associated tumorigenesis. Furthermore, cells isolated from mammary tumors induced by Neu in mice genetically lacking RPTPepsilon appear less transformed and proliferate less well than corresponding mammary tumor cells isolated from mice expressing the phosphatase. At the molecular level, RPTPepsilon dephosphorylates and activates Src and the related kinases Yes and Fyn, and the activities of these kinases are significantly reduced in tumor cells lacking RPTPepsilon. 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 RPTPepsilon. RPTPepsilon 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 RPTPepsilon to activate Src, but appears not to affect the activity of RPTPepsilon towards unrelated substrates. We conclude that a Neu-RPTPepsilon-Src pathway exists in mouse mammary tumor cells, in which Neu phosphorylates RPTPepsilon thereby driving the phosphatase to specifically activate Src family kinases and to assist in maintaining the transformed phenotype.

Epidermal Growth Factor Receptor (EGFR)-mediated Positive Feedback of Protein-tyrosine Phosphatase ϵ (PTPϵ) on ERK1/2 and AKT Protein Pathways Is Required for Survival of Human Breast Cancer Cells

“…Cells from mammary epithelial tumors initiated by HER2 in PTP⑀ knock-out mice confirmed these findings by appearing less transformed morphologically and with reduced cell proliferation (25). Together, these findings suggest that PTP⑀ is necessary for the fully transformed phenotype of HER2-induced mouse mammary tumor cells (4).…”

“…From our screening, we found PTP⑀ of special interest since this PTP had previously been related with the transformation of mouse mammary tumors (4). However, the association of PTP⑀ with human breast cancer has not been studied in detail.…”

High-resolution crystal structures of the D1 and D2 domains of protein tyrosine phosphatase epsilon for structure-based drug design

“…Among these, PTP" has been viewed as a promising candidate because it is overexpressed in murine mammary tumors and experiments have demonstrated that PTP" plays a positive role in cell growth and survival in MCF-7 cells and other breast cancer cell lines (Elson, 1999(Elson, , 2017Elson & Leder, 1995). Additional data have shown that PTP" (and the closely related PTP) are positive regulators of HER2mediated and Src-mediated signaling in breast cancer cells (Parsons & Parsons, 2004;Berman-Golan et al, 2008). Src is a major player in breast cancer, and dephosphorylation of its C-terminal regulatory phosphotyrosine (pTyr530) by PTP" triggers a cascade of events that lead to the activation of Src, which favors a transformed phenotype (Espada & Martín-Pé rez, 2017).…”

Expression of protein-tyrosine phosphatases in Acute Myeloid Leukemia cells: FLT3 ITD sustains high levels of DUSP6 expression

“…Several types of alterations of specific PTP functions have been reported in cancer cells, including gene deletion, allele loss, reduced expression by promoter methylation, or inactivation by point mutation or oxidation, all leading to loss-of function [1,2]. Upregulation of expression, or gain-of-function mutations have also been found for members of the PTP family, which have been shown or presumed to promote oncogenesis [1-4]. …”