A major role for the protein tyrosine kinase JAK1 in the JAK/STAT signal transduction pathway in response to interleukin-6

D. Guschin, N. Rogers, J. Briscoe, B. Witthuhn, D. Watling, F. Horn, S. Pellegrini, K. Yasukawa, P. Heinrich, G. R. Stark, J. N. Ihle, I. M. Kerr

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340 Scopus citations

Abstract

The protein tyrosine kinases JAK1, JAK2 and Tyk2 and STATs (signal transducers and activators of transcription) 1 and 3 are activated in response to interleukin-6 (IL-6) in human fibrosarcoma cells. In mutant cells lacking JAK1, JAK2 or Tyk2, the absence of one kinase does not prevent activation of the others; activation does not, therefore, involve a sequential three-kinase cascade. In the absence of JAK1, the phosphorylation of the gp130 subunit of the IL-6 receptor and the activation of STATs 1 and 3 are greatly reduced, JAK1 is also necessary for the induction of IRF1 mRNA, thus establishing a requirement for the JAK/STAT pathway in the IL-6 response. JAK2 and Tyk2 although activated cannot, in the absence of JAK1, efficiently mediate activation of STATs 1 and 3. A kinase-negative mutant of JAK2 can, however, inhibit such activation, and ancillary roles for JAK2 and Tyk2 are not excluded. A major role for JAK1 and the non-equivalence of JAK1 and JAK2 in the IL-6 response pathway are, nevertheless, clearly established for these cells.

Original languageEnglish (US)
Pages (from-to)1421-1429
Number of pages9
JournalEMBO Journal
Volume14
Issue number7
DOIs
StatePublished - 1995

Keywords

  • Cytokines
  • JAKs
  • Mutants
  • STATs
  • Signal transduction

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