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-4Rα, IRS-1, IRS-2, and Stat6 in appropriate cell types. However, the protein-tyrosine phosphatases (PTPs) that dephosphorylate these proteins and terminate signaling remained unidentified. We have noted that IL-4-dependent activation of Stat6 is sustained longer in fibroblasts than in lymphoid cells. Because Shp-1, an SH2 domain-containing PTP, is expressed primarily in hematopoietic cells, we examined whether Shp-1 activity could regulate IL-4-dependent cell signaling. Expression of an Shp-1 transgene in NIH 3T3 cells markedly reduces both IL-4-dependent Stat6 activation and Stat6-mediated transcription of IL-4-responsive genes. In accord with this, IL-4 treatment of bone marrow-derived macrophages from viable motheaten mice that express substantially 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 null mutant) mice compared with normal pre-B cells derived from control animals. These data clearly implicate Shp-1 in the negative regulation of the IL-4/IL-13-activated Jak-Stat pathway.

• Publication year

  1998

• Venue

  Journal of Biological Chemistry

• Publication date

  1998-12-18

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1074/JBC.273.51.33893PMID 9852037
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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