JAKs, STATs and signal transduction in response to the interferons and other cytokines.

The isolation and complementation of mutant human cell lines has established an essential role for the JAK (Janus kinase) family of protein tyrosine kinases and STAT (signal transduction and transcription) factors in the Interferon response pathways. Activation of STATs by JAKs occurs in receptor complexes at the cell membrane. Activated STATs form homo- or heterodimers and, with or without additional factors, migrate to the nucleus to initiate transcription. Different STAT combinations interact differentially with related DNA response elements. Signalling pathways of this novel type are likely utilized by a wide variety of polypeptide ligands. Data from the IL2, IL6 and IFN systems indicate a major role for the tyrosine phosphorylated receptor/JAK complexes (rather than substrate specificity of the JAKs per se) in STAT selection. The mutant cell lines lacking individual JAKs and STATs are being used together with kinase-negative JAK mutants which differentially affect the IFN-gamma, and IFN-alpha beta and IL-6 pathways in the further analysis of these and additional systems.