Protein Tyrosine Phosphatase Meg2 Dephosphorylates Signal Transducer and Activator of Transcription 3 and Suppresses Tumor Growth in Breast Cancer

Fuqin Su; Fangli Ren; Yu Rong; Yangmeng Wang; Yongtao Geng; Yinyin Wang; Mengyao Feng; Yanfang Ju; Yi Li; Zhizhuang J Zhao; Kun Meng; Zhijie Chang


Breast Cancer Res. 2012;14(2):R38 

In This Article

Abstract and Introduction


Introduction: Signal 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.
Methods: Immunoprecipitation 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.
Results: PTPMeg2 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).
Conclusions: PTPMeg2 is an important phosphatase for the dephosphorylation of STAT3 and plays a critical role in breast cancer development.


STAT3 is crucial in regulating cell growth, differentiation and survival in response to many extracellular cytokines and growth factors.[1,2] Hyper-phosphorylation of STAT3 has been observed in a variety of hematopoietic malignancies and solid tumors, including breast cancer.[3,4] In general, latent cytoplasmic STAT3 becomes activated through phosphorylation at the residue Tyr705 by Janus Associated Kinase (JAK) or growth factor receptor-associated tyrosine kinase (Src). Phosphorylated STAT3 dimerizes through a reciprocal Src homology 2-phospho-tyrosine interaction and accumulates in the nucleus, where it activates the transcription of a wide array of genes, including Bcl-xl, cyclin D1, c-Myc and SOCS3.[5]

Most studies attributed the hyper-phosphorylation of STAT3 to over-activation of JAK or Src kinase. However, STAT3 phosphorylation is also tightly regulated by a process of dephosphorylation, which is mediated by protein tyrosine phosphatases (PTPs). A line of evidence has been provided that phosphatases play an important role in numerous signaling pathways that regulate cell proliferation, apoptosis, adhesion, and migration.[6] PTPs are a large and structurally diverse family of enzymes that catalyze the dephosphorylation of phosphorylated proteins. Previous studies indicated that protein tyrosine phosphatase 1B (PTP1B) modulates cytokine signaling pathways by dephosphorylating JAK2, TYK2, STAT5a/b,[7,8] and STAT6[9] in the nucleus. Other studies demonstrated that STAT1, STAT3 and STAT5 are dephosphorylated by SHP2[10–12] and TC-PTP (PTPN2)[13,14] in the nucleus. It appears that STAT proteins can be dephosphorylated by different phosphatases both in the cytoplasm and nucleus.[15] Importantly, aberrant expression of PTPs leads to hyper-phosphorylation of STATs in the development of human diseases, including cancers, diabetes, inflammation and infectious diseases.[16,17]

PTPMeg2 (PTPN9, protein tyrosine phosphatase, non-receptor type 9), a cytoplasmic phosphatase cloned with sequence homology to retinaldehyde-binding protein and yeast SEC14p, is reported to dephosphorylate EGFR, ErB2 and Fox-1.[18–20] Functional studies indicated that PTPMeg2 promotes intracellular secretary homotypic vesicle fusion in hematopoietic cells,[21] regulates embryonic development[22] and controls expansion of erythroid cells.[23] Other studies demonstrated that PTPMeg2 regulates insulin production, beta cell growth or insulin signaling by reducing insulin receptor dephosphorylation in type II diabetes.[18,19] Recently, two studies showed that PTPMeg2 promotes dephosphorylation of EGFR and ErbB2 thereafter to impair the activation of STAT3[20] and STAT5[20,24] in breast cancer cells. However, it remains unknown whether PTPMeg2 directly targets STAT3. In this study, we demonstrated that PTPMeg2 dephosphorylates STAT3 at the Tyr705 residue by a direct interaction. We propose that PTPMeg2 is a novel direct phosphatase for STAT3.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.