Cytokine activation of the Jak–STAT pathway. Cytokine ligation and dimerization of plasma membrane receptors results in activation of receptor-associated Jak kinases and phosphorylation of receptor cytoplasmic domain tyrosine residues. STATs dock on these phosphotyrosine motifs by means of their Src homology 2 (SH2) domains. STATs are then phosphorylated on a conserved carboxy-terminus tyrosine, dimerize, and translocate to the nucleus to activate gene transcription. Transcriptional responses can be detected within a few minutes of receptor ligation. The use of a small number of protein:protein or protein:DNA interactions between the extracellular ligand and gene promoters allows specificity in signal transduction. Jak, Janus kinase; STAT, signal transducer and activator of transcription.