The Nuclear Isoform of Protein-Tyrosine Phosphatase TC-PTP Regulates interleukin-6-mediated Signaling Pathway Through STAT3 Dephosphorylation

Biochem Biophys Res Commun. 2002 Oct 4;297(4):811-7. doi: 10.1016/s0006-291x(02)02291-x.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute-Phase Proteins / metabolism
  • Animals
  • Cell Division
  • Cell Line
  • Cell Nucleus / enzymology*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Genes, Reporter
  • Humans
  • Interleukin-6 / pharmacology*
  • Isoenzymes / metabolism
  • Kinetics
  • Luciferases / genetics
  • Mice
  • Phosphorylation
  • Polymerase Chain Reaction
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2
  • Protein Tyrosine Phosphatases / metabolism*
  • Recombinant Proteins / metabolism
  • Recombinant Proteins / pharmacology
  • STAT3 Transcription Factor
  • Signal Transduction / drug effects
  • Signal Transduction / immunology
  • Signal Transduction / physiology*
  • Substrate Specificity
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transfection
  • Tumor Cells, Cultured

Substances

  • Acute-Phase Proteins
  • DNA-Binding Proteins
  • Interleukin-6
  • Isoenzymes
  • Recombinant Proteins
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Stat3 protein, mouse
  • Trans-Activators
  • Luciferases
  • PTPN2 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2
  • Protein Tyrosine Phosphatases
  • Ptpn2 protein, mouse