A MAJOR ROLE FOR THE PROTEIN-TYROSINE KINASE JAK1 IN THE JAK STAT SIGNAL-TRANSDUCTION PATHWAY IN RESPONSE TO INTERLEUKIN-6/

The protein tyrosine kinases JAK1, JAK2 and Tyk2 and STATs (signal tra nsducers and activators of transcription) 1 and 3 are activated in res ponse to interleukin-6 (IL-6) in human fibrosarcoma cells. In mutant c ells lacking JAK1, JAK2 or Tyk2, the absence of one kinase does not pr event activation of the others; activation does not, therefore, involv e a sequential three-kinase cascade. In the absence of JAK1, the phosp horylation of the gp130 subunit of the IL-6 receptor and the activatio n 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/S TAT pathway in the IL-6 response. JAK2 and Tyk2 although activated can not, in the absence of JAK1, efficiently mediate activation of STATs 1 and 3. A kinase-negative mutant of JAK2 can, however, inhibit such ac tivation, and ancillary roles for JAK2 and Tyk2 are not excluded. A ma jor role for JAK1 and the nonequivalence of JAK 1 and JAK2 in the IL-6 response pathway are, nevertheless, clearly established for these cel ls.