Kinase-negative mutants of JAK1 can sustain interferon-gamma-inducible gene expression but not an antiviral state.

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Abstract
The receptor‐associated protein tyrosine kinases JAK1 and JAK2 are both required for the interferon (IFN)‐gamma response. The effects of expressing kinase‐negative JAK mutant proteins on signal transduction in response to IFN‐gamma in wild‐type cells and in mutant cells lacking either JAK1 or JAK2 have been analysed. In cells lacking endogenous JAK1 the expression of a transfected kinase‐negative JAK1 can sustain substantial IFN‐gamma‐inducible gene expression, consistent with a structural as well as an enzymic role for JAK1. Kinase‐negative JAK2, expressed in cells lacking endogenous JAK2, cannot sustain IFN‐gamma‐inducible gene expression, despite low level activation of STAT1 DNA binding activity. When expressed in wild‐type cells, kinase‐negative JAK2 acts as a dominant‐negative inhibitor of the IFN‐gamma response. Further analysis of the JAK/STAT pathway suggests a model for the IFN‐gamma response in which the initial phosphorylation of JAK1 and JAK2 is mediated by JAK2, whereas phosphorylation of the IFN‐gamma receptor is normally carried out by JAK1. The efficient phosphorylation of STAT 1 in the receptor‐JAK complex may again depend on JAK2. Interestingly, a JAK1‐dependent signal, in addition to STAT1 activation, appears to be required for the expression of the antiviral state.