Signaling by the cytokine receptor superfamily just another kinase story

Abstract

Many cytokines initiate cellular responses through their interaction with members of the cytokine receptor superfamily. This family of receptors contains no catalytic domains in the cytoplasmic domain, but all couple ligand binding to tyrosine phosphorylation, and this activity requires a membrane-proximal region that contains some similarity among the receptors. Recent studies have shown that members of the JAK family of protein tyrosine kinases associate with the membraneproximal region, are rapidly tyrosine-phosphorylated following ligand binding, and their in vitro kinase activity is activated. The JAK family of kinases is characterized by two kinase domains, only one of which contains all of the hallmarks of active kinases. This family of 130-kD kinases lacks SH2 or SH3 domains, but family members contain extensive homology in the large amino terminal region. Individual receptors associate with, or require, one or more of the three known family members including JAKI, JAK2, and tyk2. Putative substrates of the JAK family of kinases include the 91-kD and 113-kD proteins of the interferon-stimulated transcription complex ISGF3 that, when tyrosinephosphorylated, migrate to the nucleus and participate in the activation of gene transcription. Recent evidence suggests that the 91- and 113-kD proteins are members of a large family of genes that are potential substrates o f JAK family members and may regulate a variety o f genes involved in cell growth, differentiation, or function. Together the data provide a new, generalized model for the mechanisms by which cytokines that utilize receptors of the cytokine receptor superfamily regulate cellular activity.