Protein tyrosine phosphatase Meg2 dephosphorylates signal transducer and activator of transcription 3 and suppresses tumor growth in breast cancer

Abstract

IntroductionSignal transducer and activator of transcription 3 (STAT3) is over-activated or phosphorylated in breast cancers. The hyper-phosphorylation of STAT3 was attributed to either up-regulated phosphorylation by several tyrosine-kinases or down-regulated activity of phosphatases. Although several factors have been identified to phosphorylate STAT3, it remains unclear how STAT3 is dephosphorylated by PTPMeg2. The aim of this study was to determine the role of PTPMeg2 as a phosphatase in regulation of the activity of STAT3 in breast cancers.MethodsImmunoprecipitation assays were used to study the interaction of STAT3 with PTPMeg2. A series of biochemistry experiments were performed to evaluate the role of PTPMeg2 in the dephosphorylation of STAT3. Two breast cancer cell lines MCF7 (PTPMeg2 was depleted as it was endogenously high) and MDA-MB-231 (PTPMeg2 was overexpressed as it was endogenously low) were used to compare the level of phosphorylated STAT3 and the tumor growth ability in vitro and in vivo. Samples from breast carcinoma (n = 73) were subjected to a pair-wise Pearson correlation analysis for the correlation of levels of PTPMeg2 and phosphorylated STAT3.ResultsPTPMeg2 directly interacts with STAT3 and mediates its dephosphorylation in the cytoplasm. Over-expression of PTPMeg2 decreased tyrosine phosphorylation of STAT3 while depletion of PTPMeg2 increased its phosphorylation. The decreased tyrosine phosphorylation of STAT3 is coupled with suppression of STAT3 transcriptional activity and reduced tumor growth in vitro and in vivo. Levels of PTPMeg2 and phosphorylated STAT3 were inversely correlated in breast cancer tissues (P = 0.004).ConclusionsPTPMeg2 is an important phosphatase for the dephosphorylation of STAT3 and plays a critical role in breast cancer development.

Protein tyrosine phosphatase PTPN9 regulates erythroid cell development through STAT3 dephosphorylation in zebrafish

“…S4C. However, STAT5 phosphorylation was unchanged in this condition, which is consistent with our previous observation that PTPN9 interacts very weakly with STAT5 (Su et al, 2012). Another study showed that PTPN9 preferentially associates with JAK1 but not TYK2 and JAK2 (Hao et al, 2012).…”

“…Our previous work has shown that PTPN9 directly dephosphorylates STAT3 in breast cancer cells (Su et al, 2012). Because STAT3 plays an important role in mammalian hematopoiesis, we hypothesized that Ptpn9a might also dephosphorylate Stat3 during zebrafish hematopoiesis.…”

“…shRNA against human GATA1 (shGATA1) and human ZBP-89 (shZBP-89) were designed as described previously (Woo et al, 2011). Human PTPN9, PTPN9C515S (a dominant-negative mutant of human PTPN9; N9CS), STAT3, STAT3Y705F (a dominant-negative STAT3), STAT3CA (constitutively active STAT3 with the double mutation A661C N663C) and shPTPN9 (shRNA against human PTPN9; shN9) constructs have been described previously (Su et al, 2012).…”

“…Previous studies have shown that PTPN9 dephosphorylates NSF, FOXO1, ERBB2, EGFR and VEGFR2 for different functions, such as promoting homotypic vesicle fusion (Huynh et al, 2004), mediating insulin signaling in hepatocytes (Cho et al, 2006), suppressing breast cancer cell growth (Yuan et al, 2010) and regulating endothelial cell function (Hao et al, 2012). Recently, we have shown that PTPN9 directly interacts with STAT3 and mediates its dephosphorylation in breast cancer cells (Su et al, 2012). Overexpression of PTPN9 decreases tyrosine phosphorylation of STAT3, whereas depletion of PTPN9 increases its phosphorylation.…”

The regulatory roles of phosphatases in cancer

“…Genetically silencing PTPN12 induces transformation and disrupts acinar formation in mammary epithelial cells (236). Levels of cytoplasmic protein tyrosine phosphatase non-receptor type 9 (PTPN9) inversely correlate with STAT3 in BC tissue (237). PTPN9 has been reported to inactivate STAT3 following EGFR dephosphorylation in breast cancer cells (238), suggesting that PTPN9 may play a critical role in BC development.…”