JAKS AND STATS IN CYTOKINE SIGNALING

Hematopoiesis is regulated through the binding of cytokines to recepto rs of the cytokine receptor superfamily, Although lacking catalytic do mains, members of the cytokine receptor superfamily mediate ligand-dep endent activation of protein tyrosine phosphorylation through their as sociation and activation of members of the Janus kinase (Jak) family o f protein tyrosine kinases. The activated Jaks phosphorylate the recep tors which creates docking sites for SH2-containing signaling proteins which are tyrosine phosphorylated following their association with th e complex. Among the substrates of tyrosine phosphorylation are member s of the signal transducers and activators of the transcription family of proteins (Stats). Various cytokines induce the tyrosine phosphoryl ation and activation of one or more of the seven family members, The p attern of Stat activation provides a level of cytokine individuality t hat is not observed in the activation of other signaling pathways. The role of various Stats in the biological responses to cytokines has be en assessed through the analysis of receptor mutations which disrupt S tat activation and more recently by disruption of the genes in mice. O ur results have demonstrated that the activation of Stat5a and Stat5b by erythropoietin is critical for the activation of a number of immedi ate early genes but is not required for a mitogenic response, Mice in which the genes for Stat4 and Stat6 are disrupted are viable but lack functions that are mediated by interleukin 12 (IL-12) or IL-4, respect ively, suggesting that these Stats perform very specific functions in immune responses.