The nuclear isoform of protein-tyrosine phosphatase TC-PTP regulates interleukin-6-mediated signaling pathway through STAT3 dephosphorylation.

Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-Ku Kita 12 Nishi 6, Sapporo 060-0812, Japan.
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.
Mesh Terms:
Acute-Phase Proteins, Animals, Cell Division, Cell Line, Cell Nucleus, DNA-Binding Proteins, Genes, Reporter, Humans, Interleukin-6, Isoenzymes, Kinetics, Luciferases, Mice, Phosphorylation, Polymerase Chain Reaction, Protein Tyrosine Phosphatase, Non-Receptor Type 2, Protein Tyrosine Phosphatases, Recombinant Proteins, STAT3 Transcription Factor, Signal Transduction, Substrate Specificity, Trans-Activators, Transfection, Tumor Cells, Cultured
Biochem. Biophys. Res. Commun. Oct. 04, 2002; 297(4);811-7 [PUBMED:12359225]
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