A Major Role for the Protein Tyrosine Kinase JAK1 in the JAK/STAT Signal Transduction Pathway in Response to interleukin-6

EMBO J. 1995 Apr 3;14(7):1421-9.

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 nonequivalence of JAK1 and JAK2 in the IL-6 response pathway are, nevertheless, clearly established for these cells.

MeSH terms

  • Adolescent
  • Base Sequence
  • Blotting, Western
  • Cell Line
  • DNA-Binding Proteins / metabolism*
  • Electrophoresis, Polyacrylamide Gel
  • Enzyme Activation
  • Fibrosarcoma
  • Humans
  • Interleukin-6 / pharmacology*
  • Janus Kinase 1
  • Janus Kinase 2
  • Molecular Sequence Data
  • Mutagenesis
  • Phosphoproteins / isolation & purification
  • Phosphoproteins / metabolism
  • Phosphotyrosine
  • Protein-Tyrosine Kinases / metabolism*
  • Proteins / metabolism
  • Proto-Oncogene Proteins*
  • STAT1 Transcription Factor
  • STAT3 Transcription Factor
  • Signal Transduction* / drug effects
  • TYK2 Kinase
  • Trans-Activators / metabolism*
  • Transfection
  • Tumor Cells, Cultured
  • Tyrosine / analogs & derivatives
  • Tyrosine / metabolism

Substances

  • DNA-Binding Proteins
  • Interleukin-6
  • Phosphoproteins
  • Proteins
  • Proto-Oncogene Proteins
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Trans-Activators
  • Phosphotyrosine
  • Tyrosine
  • Protein-Tyrosine Kinases
  • JAK1 protein, human
  • JAK2 protein, human
  • Janus Kinase 1
  • Janus Kinase 2
  • TYK2 Kinase
  • TYK2 protein, human