Convergence of signaling transduced by prolactin (PRL)/cytokine chimeric receptors on PRL-responsive gene transcription.
Ligand binding to cytokine receptors rapidly triggers tyrosine phosphorylation of Janus family tyrosine kinases (Jaks) and signal transducers and activators of transcription (Stats). Jak2 activation is mediated by PRL receptor homodimers as well as by receptors for the interleukin (IL)-3, IL-5, and granulocyte macrophage-colony stimulating factor, which share the common beta c-subunit. Otherwise, Jak1 and Jak3 are involved in IL-2 signaling through heterodimerization of the IL-2 receptor-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 cytoplasmic domains of the IL-2R beta or beta c-chains transduce in response to PRL tyrosine phosphorylation and activation of Jak1 and Jak2, respectively. Tyrosine phosphorylation of Stat5, activation of its DNA-binding activity assessed in bandshift experiments using a lactogenic hormone 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 results demonstrate that distinct cytoplasmic domains of these cytokine receptors elicit convergent signaling pathways and provide evidence that beta c and IL-2R beta function as a complete signal transducer. Our data strengthen previous observations that Stat5 activation is not dependent on the activation of a specific Jak kinase and also suggest that neither Jak3 nor gamma c have a specific role in this process.
Ferrag
F
F
INSERM U. 344, Faculté de Médecine Necker, Paris, France.
Chiarenza
A
A
Goffin
V
V
Kelly
P A
PA
D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003432:Cross-Linking Reagents; D004268:DNA-Binding Proteins / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D013006:Growth Hormone / Q000494:pharmacology*; D006801:Humans; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D053616:Janus Kinase 3; D008156:Luciferases / Q000096:biosynthesis; D046911:Macromolecular Substances; D008894:Milk Proteins; D008969:Molecular Sequence Data; D011388:Prolactin / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D011817:Rabbits; D051381:Rats; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis / Q000502:physiology*; D011981:Receptors, Prolactin / Q000096:biosynthesis / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D050799:STAT5 Transcription Factor; D012756:Sheep; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection
D003432:Cross-Linking Reagents; D004268:DNA-Binding Proteins; C507936:Jak3 protein, rat; D046911:Macromolecular Substances; D008894:Milk Proteins; D011518:Proto-Oncogene Proteins; D015375:Receptors, Interleukin-2; D011981:Receptors, Prolactin; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D003907:Dexamethasone; D011388:Prolactin; D013006:Growth Hormone; D008156:Luciferases; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507924:JAK2 protein, human; C507933:JAK3 protein, human; C507906:Jak1 protein, rat; C507927:Jak2 protein, rat; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D053616:Janus Kinase 3