Several distinct classes of cytokine receptors engage Jak kinases as primary effectors. Among type 1 receptors, Janus-activated kinase (Jak) recruitment is mediated by membrane-proximal cytoplasmic domains, which typically contain conserved box motifs. In the erythropoietin receptor (Epo-R), two such motifs (box1 and box2) have been suggested to be essential for the activation of Jak2 and mitogenesis. Presently, an Epo-R chimera containing the extracellular and box1 domains of the Epo-R (Jak2-associated receptor) and the box2 and carboxyl-terminal domains of the interleukin 2 beta-receptor (IL2beta-R; a Jak1-associated subunit) is shown to activate Jak2. Interestingly, Jak2 also was activated in FDC-P1 cells by a control Epo-R chimera containing the complete IL2beta-R cytoplasmic domain, and mitogenesis was supported by each of these above chimeras. By comparison, in BaF3 cells expressing IL2 receptor alpha and gamma subunits, an ectopically expressed IL2beta-R chimera containing the box1 domain of the Epo-R, activated Jak2 and Jak3 and was as mitogenically active as the wild-type IL2beta-R (Jak1 and Jak3 activation). Thus, the box1 domain of the Epo-R specifies Jak2 activation and functions efficiently within a heterologous IL2 receptor complex that normally activates Jak1 and Jak3.
