JAK-STAT signal transduction in response to type I and type II IFNs. Upon binding of ligand, IFN receptor–associated Janus kinases (JAKs) are activated and phosphorylate receptor chains on tyrosine. Cytoplasmic signal transducers and activators of transcription (STATs) bind to the phosphorylated receptors with their SH2 domains. JAKs associated with the type I IFN receptor (IFNAR) then phosphorylate STAT1 and STAT2 on tyrosine, causing the formation of predominantly STAT1-STAT2 heterodimers, and of STAT1 homodimers. IFN-γ receptor–associated (IFNGR-associated) JAKs phosphorylate STAT1, leading to the formation of STAT1 homodimers. STAT dimers translocate to the cell nucleus. Thereafter, STAT1-STAT2 heterodimers associate with a third protein, IRF9, and bind one class of type I IFN response elements, the ISRE, whereas STAT1 homodimers activate gene expression by binding to another class of IFN response elements, the GAS.