Involvement of tyrosine phosphatase PTP1D in the inhibition of interleukin-6-induced Stat3 signaling by alpha-thrombin.
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.
Gunaje
J J
JJ
Icogen Corporation, 454 North 34th Street, Seattle, WA 98103, USA. gunajej@icogen.com
Bhat
G J
GJ
D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004336:Drug Antagonism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D053683:Oncostatin M; D010455:Peptides / Q000494:pharmacology; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011233:Precipitin Tests; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000502:physiology*; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D013917:Thrombin / Q000494:pharmacology*; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014638:Vanadates / Q000494:pharmacology; D000093242:Interleukin-6 Inhibitors
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D007371:Interferon-gamma; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D053683:Oncostatin M; D010455:Peptides; D019000:Phosphotyrosine; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D013917:Thrombin; D015534:Trans-Activators; D014638:Vanadates; D000093242:Interleukin-6 Inhibitors; C508351:OSM protein, human; C494079:STAT1 protein, human; C494086:STAT3 protein, human; C509249:PTPN6 protein, human