Janus kinases in cytokine signalling

Abstract

Hematopoiesis is largely regulated by the binding of cytokines to receptors of the cytokine receptor superfamily. Although lacking catalytic domains, members of the cytokine receptor superfamily mediate ligand dependent activation of tyrosine phosphorylation which is critical for all receptor functions. Recent studies have demonstrated that this is mediated through the association and activation of members of the Janus kinase (Jak) family of protein tyrosine kinases. The activated Jaks phosphorylate the receptors, creating docking sites for SH2 containing signalling proteins which are tyrosine phosphorylated following their association with the receptor complex. Among the substrates of tyrosine phosphorylation are members of the signal transducers and activators of transcription family of proteins (Stats). Various cytokines induce the tyrosine phosphorylation and activation of one or more of the six family members. The pattern of Stat activation provides a level of cytokine individuality that is not observed in the activation of other signalling pathways. Although not required for mitogenic responses, it is speculated that the Stats may mediate many of the cytokine specific functional responses of hematopoietic cells.