Protein Tyrosine Phosphatases as Potential Regulators of STAT3 Signaling

Abstract

The signal transducer and activator of transcription 3 (STAT3) protein is a major transcription factor involved in many cellular processes, such as cell growth and proliferation, differentiation, migration, and cell death or cell apoptosis. It is activated in response to a variety of extracellular stimuli including cytokines and growth factors. The aberrant activation of STAT3 contributes to several human diseases, particularly cancer. Consequently, STAT3-mediated signaling continues to be extensively studied in order to identify potential targets for the development of new and more effective clinical therapeutics. STAT3 activation can be regulated, either positively or negatively, by different posttranslational mechanisms including serine or tyrosine phosphorylation/dephosphorylation, acetylation, or demethylation. One of the major mechanisms that negatively regulates STAT3 activation is dephosphorylation of the tyrosine residue essential for its activation by protein tyrosine phosphatases (PTPs). There are seven PTPs that have been shown to dephosphorylate STAT3 and, thereby, regulate STAT3 signaling: PTP receptor-type D (PTPRD), PTP receptor-type T (PTPRT), PTP receptor-type K (PTPRK), Src homology region 2 (SH-2) domain-containing phosphatase 1(SHP1), SH-2 domain-containing phosphatase 2 (SHP2), MEG2/PTP non-receptor type 9 (PTPN9), and T-cell PTP (TC-PTP)/PTP non-receptor type 2 (PTPN2). These regulators have great potential as targets for the development of more effective therapies against human disease, including cancer.

Progranulin sustains STAT3 hyper‐activation and oncogenic function in colorectal cancer cells

“…A), thus suggesting a role for progranulin in modulating STAT3 dephosphorylation. More in‐depth experimentation revealed that intracellular progranulin restrained the ability of key STAT3 tyrosine phosphatases (i.e., SHP‐1 and SHP‐2) (Kim et al ., ) to interact with the transcription factor (Fig. B–D), likely contributing to STAT3 hyper‐activation.…”

“…Thus, targeting progranulin might represent a different approach to achieve this goal. However, we cannot exclude the possibility that progranulin might affect other STAT3‐targeting tyrosine phosphatases (Kim et al ., ), and such an effect has some contribution to progranulin‐mediated STAT3 hyper‐activation. Further and more in‐depth studies beyond those presented here will be needed to answer this question.…”

Effect of liraglutide on the Janus kinase/signal transducer and transcription activator (JAK/STAT) pathway in diabetic kidney disease in db/db mice and in cultured endothelial cells

“…Signal transducer and activator of transcription 3 is activated following phosphorylation at Tyr 705 . In addition, STAT3 activation can occur via phosphorylation of Ser 727 by mitogen‐activated protein kinases (MAPKs) or c‐Src non‐receptor tyrosine kinase . Both JAK1 and JAK2 are essential for STAT3 dimer formation, nuclear translocation, and DNA binding activity by phosphorylation at Tyr 705 , whereas phosphorylation at Ser 727 is through MAPK or mammalian target of rapamycin (mTOR) .…”

“…In addition, STAT3 activation can occur via phosphorylation of Ser 727 by mitogen‐activated protein kinases (MAPKs) or c‐Src non‐receptor tyrosine kinase . Both JAK1 and JAK2 are essential for STAT3 dimer formation, nuclear translocation, and DNA binding activity by phosphorylation at Tyr 705 , whereas phosphorylation at Ser 727 is through MAPK or mammalian target of rapamycin (mTOR) . Moreover, p‐STAT3 (Ser 727 ) can be transported into the mitochondria instead of the nucleus, where it contributes to cell homeostasis .…”

The role of T‐cell protein tyrosine phosphatase in epithelial carcinogenesis

“…Within the STAT family of transcription factors, STAT3 is the most well‐known because it has been established as a major oncogenic protein that plays multifunctional roles in cell proliferation, autophagy, differentiation, and cell survival. It is mainly activated by the IL‐6 family of cytokines, epidermal growth factor, and leptin . Yamamoto et al were the first to find that STAT3 is a substrate of TC‐PTP.…”