SIGNALING THROUGH THE HEMATOPOIETIC CYTOKINE RECEPTORS

Hematopoiesis is regulated through the interaction of a variety of gro wth factors with specific receptors of the cytokine receptor superfami ly. Although lacking catalytic domains, all the receptors couple ligan d binding to the rapid induction of protein tyrosine phosphorylation. This is mediated through a novel family of protein tyrosine kinases te rmed the Janus kinases (Jaks) which associate with the receptors and a re activated following ligand binding. Depending upon the cytokine/rec eptor system, one or more of the four known Jaks (Jak1, Jak2, Jak3, Ty k2) is/are involved. The activated Jaks phosphorylate both themselves and the receptor subunits, creating docking sites for SH2-containing p roteins including SHC, which couples receptor engagement to activation of the ras pathway, and HCP, a protein tyrosine phosphatase which neg atively affects the response. In addition, the Jaks phosphorylate one or more of a family of signal transducers and activators of transcript ion (Stats). Phosphorylation of Stats induces their nuclear translocat ion and DNA-binding activity. Activation of Stats is independent of ac tivation of the ras pathway and represents a novel signaling pathway c orrelated with mitogenesis.