To investigate the role of protein tyrosine phosphatases in IL-4Rα-chain expression and signaling, we first established that SHP-1, but not SHP-2, coimmunoprecipitated with anti-IL-4Rα chain Abs in extracts prepared from resting lymphocytes. We further observed that the protein tyrosine phosphatase inhibitors Na 3 VO 4 and pervanadate blocked the striking induction of IL-4Rα-chain expression that is mediated by IL-4. However, Na 3 VO 4 did not diminish IL-4-induced Stat6 phosphorylation nor did it block the IL-4-mediated increase in IL-4Rα-chain mRNA. The striking inhibition in total cellular IL-4Rα-chain and in cell surface IL-4 receptors was associated with an inhibition of biosynthetic labeling of IL-4Rα-chain after a 30-min pulse with [35 S] methionine, indicating that reduction of IL-4Rα-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-4Rα-chain protein expression by phosphatase may provide a novel means to regulate IL-4 responsiveness.