CONVERGENCE OF SIGNALING TRANSDUCED BY PROLACTIN (PRL) CYTOKINE CHIMERIC RECEPTORS ON PRL-RESPONSIVE GENE-TRANSCRIPTION/

Ligand binding to cytokine receptors rapidly triggers tyrosine phospho rylation of Janus family tyrosine kinases (Jaks) and signal transducer s and activators of transcription (Stats). Jak2 activation is mediated by PRL receptor homodimers as well as by receptors for the interleuki n (IL)-3, IL-5, and granulocyte macrophage-colony stimulating factor, which share the common beta(c)-subunit. Otherwise, Jak1 and Jak3 are i nvolved in IL-2 signaling through heterodimerization of the IL-2 recep tor-beta (IL-2R beta) and gamma(c)-chains. Stat5, a member of the Stat family, confers the PRL response on milk protein genes. Here we show that chimeric PRL receptors that contain the transmembrane and cytopla smic domains of the IL-2R beta or beta(c)-chains transduce in response to PRL tyrosine phosphorylation and activation of Jak1 and Jak2, resp ectively. Tyrosine phosphorylation of Stat5, activation of its DNA-bin ding activity assessed in bandshift experiments using a lactogenic hor mone responsive region (LHRR) probe, and transcriptional induction of a beta-casein promoter luciferase construct in stably transfected CHO cells are observed with both chimeras upon PRL stimulation. Our result s demonstrate that distinct cytoplasmic domains of these cytokine rece ptors elicit convergent signaling pathways and provide evidence that b eta(c) and IL-2R beta function as a complete signal transducer. Our da ta strengthen previous observations that Stat5 activation is not depen dent on the activation of a specific Jak kinase and also suggest that neither Jak3 nor gamma(c) have a specific role in this process.