Abstract

Many cytokines mediate their biological effects through interaction with a distinct family of receptors termed the cytokine receptor superfamily. Although members of this family lack catalytic domains, they couple ligand binding to tyrosine phosphorylation. Recent studies have shown that a novel family of cytoplasmic protein tyrosine kinases, termed the Janus kinases (Jaks), associate with the cytokine receptors and are catalytically activated after ligand binding. The activated Jaks phosphorylate and activate members of a novel family of transcription factors termed signal transducers and activators of transcription (Stats). In addition, many cytokines induce the phosphorylation of SHC, Vav and the p85 subunit of PI-3 kinase. The region of the receptors proximal to the cytoplasmic membrane is required for Jak association, mitogenesis, Stat activation and Vav phosphorylation. The membrane-distal region, which contains the major sites of tyrosine phosphorylation, is required for phosphorylation of SHC and p85, not for mitogenesis, thus allowing functional dissection of the signaling pathways activated by cytokines.