Protein-tyrosine phosphatase Shp-1 is a negative regulator of IL-4- and IL-13-dependent signal transduction

Binding of interleukin (IL)-4 to its transmembrane receptor results in the Jak-mediated tyrosine phosphorylation of a number of protein components of the IL-4 signaling cascade, including Jak1, Jak2, Jak3,Tyk2, IL-4R alpha, I RS-1, IRS-2, and Stat6 in appropriate cell types. However, the protein-tyro sine phosphatases (PTPs) that dephosphorylate these proteins and terminate signaling remained unidentified. We have noted that IL-4-dependent activati on of State is sustained longer in fibroblasts than in lymphoid cells. Beca use Shp-1, an SH2 domain-containing PTP, is expressed primarily in hematopo ietic cells, we examined whether Shp-1 activity could regulate IL-4-depende nt cell signaling. Expression of an Shp-1 transgene in NIH 3T3 cells marked ly reduces both IL-4-dependent State activation and Stat6-mediated transcri ption of IL-4-responsive genes. In accord with this, IL-4 treatment of bone marrow-derived macrophages from viable motheaten mice that express substan tially reduced levels of Shp-1 activity show remarkably enhanced activation of Stat6. In addition, Stat6 activation by IL-4 is significantly enhanced in pre-B cells derived from motheaten (Shp-1 nub mutant) mice compared with normal pre-B cells derived from control animals. These data clearly implic ate Shp-1 in the negative regulation of the IL-4/IL-13-activated Jak-Stat p athway.