Convergence of signaling transduced by prolactin (PRL)/cytokine chimeric receptors on PRL-responsive gene transcription.

Abstract

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.

Prolactin (PRL) and Its Receptor: Actions, Signal Transduction Pathways and Phenotypes Observed in PRL Receptor Knockout Mice

“…Similarly, when the C-terminal domain of Stat5 is truncated (which removes the tyrosine phosphorylation site), such mutants function as a dominant-negative (540 -542). Finally, it is noteworthy that in the specific context of cytokine chimeric receptors, JAK1 and possibly JAK3 can also phosphorylate Stat5 on tyrosine (543).…”

“…The activation of identical Stat proteins by different cytokine receptors questions the mechanisms by which specificity of signaling pathways is achieved in response to a particular hormonal stimulation. Although several cytokines (EPO, GM-CSF, GH, PRL, IL-2, IL-3, IL-5) activate the DNA-binding ability of Stat5 and/or transactivate the ␤-casein luciferase reporter gene in vitro (516,536,543,564,(567)(568)(569)(570)(571), it is unlikely that all these cytokines stimulate the synthesis of this milk protein in vivo. This suggests that different Stat combinations and/or involvement of other signal transducers direct the specificity of the final response.…”

Effects of prolactin on intracellular calcium concentration and cell proliferation in human glioma cells

“…The intracellular activation pathways of PRL-R are particularly complex and include activation of JAK2 and STAT signaling pathways (Ferrag et al, 1996;Ali, 1998). On the other hand, numerous hormones act through intracellular mediators, which ultimately appear to regulate cytosolic calcium ion concentrations ([Ca 2ϩ ] i ) by either mobilizing intracellular stores or stimulating calcium influx.…”

Atlas of the neurons that express mRNA for the long form of the prolactin receptor in the forebrain of the female rat

“…The intracellular activation pathways of these receptors are particularly complex and include activation of Jak and Stat signaling pathways (Ali et al, 1996;Ferrag et al, 1996). Prolactin can also act on the central nervous system to promote physiological and behavioral changes including the induction of maternal behavior (Bridges et al, 1990), increased food intake (Noel and Woodside, 1993), inhibition of sexual receptivity (Dudley et al, 1982), and stretch-yawning (Laping and Ramirez, 1986).…”