Receptor-associated constitutive protein tyrosine phosphatase activity controls the kinase function of JAK1

S. Jaharul Haque, Qian Wu, Winfried Kammer, Karlheinz Friedrich, Jonathan M. Smith, Ian M. Kerr, George R. Stark, Bryan R.G. Williams

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63 Citations (Scopus)

Abstract

Exposure of cells to protein tyrosine phosphatase (PTP) inhibitors causes an increase in the phosphotyrosine content of many cellular proteins. However, the level at which the primary signaling event is affected is still unclear. We show that Jaks are activated by tyrosine phosphorylation in cells that are briefly exposed to the PTP inhibitor pervanadate (PV), resulting in tyrosine phosphorylation and functional activation of Stat6 (in addition to other Stats). Mutant cell lines that lack Jak1 activity fail to support PV- mediated [or interleukin 4 (IL-4)-dependent] activation of Stat6 but can be rescued by complementation with functional Jak1. The docking sites for both Jak1 and Stat6 reside in the cytoplasmic domain of the IL-4 receptor α- chain (IL-4Rα). The glioblastoma-derived cell lines T98G, GRE, and M007, which do not express the IL-4Rα chain, fail to support Stat6 activation in response to either IL-4 or PV. Complementation of T98G cells with the IL- 4Rα restores both PV-mediated and IL-4-dependent Stat6 activation. Murine L929 cells, which do not express the γ common chain of the IL-4 receptor, support PV-mediated but not IL-4-dependent Stat6 activation. Thus, Stat6 activation by PV is an IL-4Rα-mediated, Jak1-dependent event that is independent of receptor dimerization. We propose that receptor-associated constitutive PTP activity functions to down-regulate persistent, receptor- linked kinase activity. Inhibition or deletion of PTP activity results in constitutive activation of cytokine signaling pathways.

Original languageEnglish
Pages (from-to)8563-8568
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume94
Issue number16
DOIs
Publication statusPublished - 5 Aug 1997
Externally publishedYes

Keywords

  • Interleukin 4 receptor
  • Janus kinase
  • Pervanadate
  • Protein tyrosine kinase
  • Signal transducer and activator of transcription

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