The nuclear isoform of protein-tyrosine phosphatase TC-PTP regulates interleukin-6-mediated signaling pathway through STAT3 dephosphorylation.
In the previous study, we demonstrated that the nuclear isoform of T-cell protein-tyrosine phosphatase (TC-PTP) dephosphorylated and deactivated signal transducer and activator of transcription 5a (STAT5a) and STAT5b, thereby negatively regulating prolactin (PRL)-mediated signaling pathway. In this study, we examined the involvement of the nuclear isoform of TC-PTP in interleukin-6 (IL-6)-mediated signaling pathway. IL-6 is a multifunctional cytokine that plays important roles in the immune system, hematopoiesis, and acute phase reactions, and has also implicated in IL-6-related diseases. Here, we demonstrate that IL-6-induced tyrosine-phosphorylation and activation of STAT3 were suppressed by overexpression of the nuclear isoform of TC-PTP in 293T cells. Tyrosine-phosphorylated STAT3 directly interacted with a substrate-trapping mutant of TC-PTP. Furthermore, retrovirus-mediated overexpression of the nuclear isoform of TC-PTP suppressed the IL-6-induced growth arrest of myeloid leukemia M1 cells. Endogenous TC-PTP complexed with STAT3 in the nucleus of M1 cells. These results strongly suggest that the nuclear isoform of TC-PTP may serve as a negative regulator of IL-6-mediated signaling pathway.
D000209:Acute-Phase Proteins / Q000378:metabolism; D000818:Animals; D002455:Cell Division; D002460:Cell Line; D002467:Cell Nucleus / Q000201:enzymology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D017930:Genes, Reporter; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D008156:Luciferases / Q000235:genetics; D051379:Mice; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D013379:Substrate Specificity; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured
D000209:Acute-Phase Proteins; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D007527:Isoenzymes; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D008156:Luciferases; C516649:PTPN2 protein, human; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2; D017027:Protein Tyrosine Phosphatases; C516653:Ptpn2 protein, mouse