Complementation by the protein tyrosine kinase JAK2 of a mutant cell line defective in the interferon-& gamma; signal transduction pathway

Abstract

INTERFERONS (IFNs) & alpha;/& beta; (type I) and & gamma; (type II) bind to distinct cell surface receptors¹, inducing transcription of overlapping sets of genes by intracellular pathways that have recently attracted much attention^2,3. Previous studies using cell lines selected for their inability to respond to IFN-& alpha; (ref. 4) have shown that the protein kinase Tyk2 plays a central role in the IFN & alpha;/& beta; response⁵. Here we report the isolation of the cell line & gamma;l A, selected for its inability to express IFN-& gamma;-inducible cell-surface markers, that is deficient in all aspects of the IFN-& gamma; response tested, but responds normally to IFNs & alpha; and & beta;. The mutant cells can be complemented by the expression of another member of the JAK family of protein tyro-sine kinases, JAK2 (refs 6& ndash;9). Unlike IFNs & alpha; and & beta;, IFN-& gamma; induces rapid tyrosine phosphorylation of JAK2 in wild-type cells, and JAK2 immunoprecipitates from these cells show tyrosine kinase activity. These responses are absent in & gamma;l A cells. JAK2 is therefore required for the response to IFN-& gamma; but not to IFNs & alpha; and & beta;.