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

Abstract

Background:To investigate the functional role of PTP⑀ in human breast cancer cell lines. Results: PTP⑀ was up-regulated in human breast cancer cells in an EGFR-and ERK1/2-dependent manner. PTP⑀ displayed a positive role in survival of human breast cancer cells. Conclusion: PTP⑀ generates a positive feedback regulatory loop required for survival of human breast cancer cells. Significance: PTP⑀ could be a putative target in breast cancer treatment.Increased tyrosine phosphorylation has been correlated with human cancer, including breast cancer. In general, the activation of tyrosine kinases (TKs) can be antagonized by the action of protein-tyrosine phosphatases (PTPs). However, in some cases PTPs can potentiate the activation of TKs. In this study, we have investigated the functional role of PTP⑀ in human breast cancer cell lines. We found the up-regulation and activation of receptor PTP⑀ (RPTP⑀) in MCF-7 cells and MDA-MB-231 upon PMA, FGF, and serum stimulation, which depended on EGFR and ERK1/2 activity. Diminishing the expression of PTP⑀ in human breast cancer cells abolished ERK1/2 and AKT activation, and decreased the viability and anchorage-independent growth of the cells. Conversely, stable MCF-7 cell lines expressing inducible high levels of ectopic PTP⑀ displayed higher activation of ERK1/2 and anchorage-independent growth. Our results demonstrate that expression of PTP⑀ is up-regulated and activated in breast cancer cell lines, through EGFR, by sustained activation of the ERK1/2 pathway, generating a positive feedback regulatory loop required for survival of human breast cancer cells.

RNA Sequencing Analysis Detection of a Novel Pathway of Endothelial Dysfunction in Pulmonary Arterial Hypertension

“…Dominantnegative ISG20 (interferon-stimulated exonuclease gene 20 kD) inhibits angiogenic function in human umbilical vein ECs by a less well-defined mechanism (31). Other transcripts that were reduced included GADD45B, the DNA repair protein (reviewed in Reference 32); GPCR5B, best studied in differentiation of macrophages (33); and PTPRE, a phosphatase that can up-regulate EGF receptor signaling (34). Transcripts that were increased in IPAH versus control PAECs by RNAseq include high-mobility group AT-hook 1 (HMGA1) and endothelial nitric oxide synthase (NOS3).…”

IQ Motif Containing GTPase-Activating Protein 3 (IQGAP3) Inhibits Kaempferol-Induced Apoptosis in Breast Cancer Cells by Extracellular Signal-Regulated Kinases 1/2 (ERK1/2) Signaling Activation

“…In our study, upregulation of IQGAP3 inhibited apoptosis of BC cells, accompanied with increased p-ERK1/2 and Bcl2 expression and decreased Bax expression, and Kaempferol counteracted the effect of IQGAP3 upregulation. ERK1/2, one of the most extensively studied groups of MAPKs, is a major determinant in diverse cellular processes, including apoptosis, proliferation, and survival [33,34], and has been observed to be associated with BC [35]. It has been reported that Kaempferol-induced apoptosis of BC cells involves sustained activation of ERK signaling [8], and IQGAP3 is reported to regulate cell proliferation by mediating Ras-dependent ERK signaling [17].…”

Tuning the Protein Phosphorylation by Receptor Type Protein Tyrosine Phosphatase Epsilon (PTPRE) in Normal and Cancer Cells

“…PTPRE contributes to Erk1/2 and Akt activation, improve the cell viability and colony formation of breast cancer cell lines. EGFR, Erk and PTPRE forms a positive feedback loop 52. Overexpression of PTPRE in murine mammary epithelium leads to mammary hyperplasia and higher occurance of tumor 53, suggesting that PTPRE itself is not sufficient to induce cell transformation.…”

“…In normal cells, PTPRE inhibits the activation of insulin receptor 26, 27 and PDGFB signaling 28. Unlike that in normal cells, PTPRE positively regulates the receptor tyrosine kinase EGFR signaling 52. The underlying mechanisms as to how PTPRE regulates the signaling of different receptor tyrosine kinases in opposite ways between normal and cancer cells remain obscure, and should be further explored.…”