Protein tyrosine phosphatase activity is required for IL-4 induction of IL-4 receptor alpha-chain.
To investigate the role of protein tyrosine phosphatases in IL-4Ralpha-chain expression and signaling, we first established that SHP-1, but not SHP-2, coimmunoprecipitated with anti-IL-4Ralpha chain Abs in extracts prepared from resting lymphocytes. We further observed that the protein tyrosine phosphatase inhibitors Na3VO4 and pervanadate blocked the striking induction of IL-4Ralpha-chain expression that is mediated by IL-4. However, Na3VO4 did not diminish IL-4-induced Stat6 phosphorylation nor did it block the IL-4-mediated increase in IL-4Ralpha-chain mRNA. The striking inhibition in total cellular IL-4Ralpha-chain and in cell surface IL-4 receptors was associated with an inhibition of biosynthetic labeling of IL-4Ralpha-chain after a 30- min pulse with [35S] methionine, indicating that reduction of IL-4Ralpha-chain protein resulted from either a diminished production of the receptor or a rapid degradation, possibly as a result of phosphorylation of the receptor in an early biosynthetic cellular compartment. Control of newly synthesized IL-4Ralpha-chain protein expression by phosphatase may provide a novel means to regulate IL-4 responsiveness.
Huang
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Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. hhuang@helix.nih.gov
Paul
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D000818:Animals; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000276:immunology; D015847:Interleukin-4 / Q000378:metabolism / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D008198:Lymph Nodes / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D019948:Receptors, Interleukin-4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000276:immunology; D013154:Spleen / Q000166:cytology; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology; D014638:Vanadates / Q000494:pharmacology; D018909:src Homology Domains / Q000276:immunology
D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D019948:Receptors, Interleukin-4; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D015847:Interleukin-4; D014638:Vanadates; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse; C509248:Ptpn6 protein, mouse; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases