Involvement of tyrosine phosphatase PTP1D in the inhibition of interleukin-6-induced Stat3 signaling by alpha-thrombin

Biochem Biophys Res Commun. 2001 Oct 19;288(1):252-7. doi: 10.1006/bbrc.2001.5759.


We previously demonstrated that exposure of CCL39 lung fibroblasts to alpha-thrombin inhibits interleukin-6 (IL-6)-induced tyrosine phosphorylation of Stat3 (signal transducers and activators of transcription 3) via activation of mitogen-activated protein (MAP) kinase kinase 1 [Bhat et al. (1998) Arch. Biochem. Biophys. 350, 307-314]. In this study, using CCL39/MRC-5 cells, we investigated if additional signaling intermediates are involved in alpha-thrombin's inhibitory effects on IL-6-induced Stat3 signaling. We also determined if alpha-thrombin inhibits oncostatin M (OSM)-induced Stat3/Stat1, and interferon-gamma (IFN-gamma)-induced Stat1 tyrosine phosphorylation. We demonstrate that, although both IL-6 and OSM belong to the same cytokine family, alpha-thrombin inhibited only the IL-6-induced Stat3 tyrosine phosphorylation. The tyrosine phosphatase PTP1D coprecipitated with Stat3 from alpha-thrombin + IL-6, but not from alpha-thrombin + OSM-treated cells. Pretreatment of cells with a phosphatase inhibitor reversed the inhibitory actions of alpha-thrombin, suggesting a role for PTP1D in alpha-thrombin-mediated inhibition of IL-6-induced Stat3 signaling. Interestingly, alpha-thrombin failed to inhibit OSM- and IFN-gamma-induced Stat1 tyrosine phosphorylation. Cytokine-specific inhibition of the Stat3 signaling involving MAP kinase kinase 1 and PTP1D by alpha-thrombin may play an important role in regulation of gene expression.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Line
  • Cricetinae
  • DNA-Binding Proteins / antagonists & inhibitors*
  • DNA-Binding Proteins / metabolism
  • Drug Antagonism
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Interferon-gamma / pharmacology
  • Interleukin-6 / antagonists & inhibitors*
  • Interleukin-6 / pharmacology
  • Intracellular Signaling Peptides and Proteins
  • Oncostatin M
  • Peptides / pharmacology
  • Phosphorylation
  • Phosphotyrosine / metabolism
  • Precipitin Tests
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases / physiology*
  • STAT1 Transcription Factor
  • STAT3 Transcription Factor
  • Signal Transduction* / drug effects
  • Thrombin / pharmacology*
  • Trans-Activators / antagonists & inhibitors*
  • Trans-Activators / metabolism
  • Vanadates / pharmacology


  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Interleukin-6
  • Intracellular Signaling Peptides and Proteins
  • OSM protein, human
  • Peptides
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Trans-Activators
  • Oncostatin M
  • Phosphotyrosine
  • Vanadates
  • Interferon-gamma
  • PTPN6 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases
  • Thrombin