Kinase-deficient forms of Jak1 and Tyk2 inhibit interferon alpha signaling in a dominant manner.
Signaling by interferon alpha (IFN alpha), an extracellular factor that mediates a number of anti-viral and growth-suppressive effects, requires two members of the Janus family of tyrosine kinases (JAK family): Jak1 and Tyk2. IFN alpha treatment of cells induces the rapid tyrosine phosphorylation of these two kinases, two subunits of the IFN alpha receptor, and two members of the signal transducer and activator of transcription (STAT) family of latent transcription factors. These proteins are believed to be direct substrates of one or both JAKs. Though the requirement for both Jak1 and Tyk2 in the IFN alpha-signaling cascade is well established, the order of activation and the relative contribution of the two kinases has not been elucidated completely. To address these questions, we have employed kinase-deficient mutants of both enzymes. Both mutant kinases suppress transcriptional activation as measured by an IFN alpha-dependent reporter-gene assay. Furthermore, in transient-transfection assays, the kinase-deficient versions of Tyk2 and Jak1 can act independently to inhibit STAT phosphorylation. Thus, kinase-deficient versions of JAK can act in a dominant-negative fashion to suppress IFN alpha signaling. The effects of the overexpressed mutant kinases on the phosphorylation of the kinases themselves, however, are unequal, suggesting that Jak1 functions upstream of Tyk2.
Krishnan
K
K
Department of Pathology and Irving Cancer Center, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
Pine
R
R
Krolewski
J J
JJ
D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D016898:Interferon-alpha / Q000037:antagonists & inhibitors*; D053613:Janus Kinase 1; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000502:physiology*; D011506:Proteins / Q000502:physiology*; D050795:STAT2 Transcription Factor; D015398:Signal Transduction; D053634:TYK2 Kinase; D015534:Trans-Activators / Q000378:metabolism; D015533:Transcriptional Activation; D018909:src Homology Domains
D004268:DNA-Binding Proteins; D016898:Interferon-alpha; D011506:Proteins; D050795:STAT2 Transcription Factor; D015534:Trans-Activators; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; D053613:Janus Kinase 1; D053634:TYK2 Kinase; C070139:TYK2 protein, human