COMPLEMENTATION BY THE PROTEIN-TYROSINE KINASE JAK2 OF A MUTANT-CELL LINE DEFECTIVE IN THE INTERFERON-GAMMA SIGNAL-TRANSDUCTION PATHWAY

INTERFERONS (IFNs) alpha/beta (type I) and gamma (type II) bind to dis tinct cell surface receptors1, inducing transcription of overlapping s ets of genes by intracellular pathways that have recently attracted mu ch attention2,3. 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. Her e we report the isolation of the cell line gamma1A, selected for its i nability to express IFN-gamma-inducible cell-surface markers, that is deficient in all aspects of the IFN-gamma response tested, but respond s normally to IFNs alpha and beta. The mutant cells can be complemente d by the expression of another member of the JAK family of protein tyr osine kinases, JAK2 (refs 6-9). 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 activit y. These responses are absent in gamma1A cells. JAK2 is therefore requ ired for the response to IFN-gamma but not to IFNs alpha and beta.