Serine-727 phosphorylation activates hypothalamic STAT-3 independently from tyrosine-705 phosphorylation

Andreas Breit, Valeria Besik, Hans Jürgen Solinski, Susanne Muehlich, Evi Glas, Stephen J Yarwood, Thomas Gudermann

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    19 Citations (Scopus)


    Transcriptional activity of signal transducer and activator of transcription-3 (STAT-3) is a key element in the central regulation of appetite and energy homeostasis. Activation of hypothalamic STAT-3 has been attributed to cytokine-promoted phosphorylation at tyrosine-705 (Tyr-705). In nonhypothalamic cells, STAT-3 is also phosphorylated at serine-727 (Ser-727), but the functional significance of Ser-727 in the regulation of hypothalamic STAT-3 is not known. We used 2 hypothalamic cell lines and analyzed the effects of various hormones on STAT-3-dependent reporter gene activity and observed that IFN-γ, epidermal growth factor (EGF), and bradykinin (BK) induce similar STAT-3 reporter activation. EGF and BK solely increased Ser-727 and IFN-γ increased Tyr-705 phosphorylation of STAT-3. Specific inhibition of ERK-1/2 activity blocked EGF- and BK-induced STAT-3 activation and Ser-727 phosphorylation. BK-induced ERK-1/2 activation occurred via EGF receptor transactivation. Consequently, the BK-mediated effects on STAT-3 were blocked by a specific EGF receptor antagonist. Next, we analyzed the effects of IFN-γ and EGF on the expression of the STAT-3-dependent genes thyroliberin-releasing hormone and suppressors of cytokine signaling-3. EGF but not IFN-γ enhanced thyroliberin-releasing hormone expression via STAT-3. With regard to suppressors of cytokine signaling-3, we observed prolonged expression induced by IFN-γ and a transient effect of EGF that required coactivation of the activator protein-1. Thus, EGF-promoted Ser-727 phosphorylation by ERK-1/2 is not only sufficient to fully activate hypothalamic STAT-3, but, in terms of targeted genes and required cofactors, entails distinct modes of STAT-3 actions compared with IFN-γ-induced Tyr-705 phosphorylation.

    Original languageEnglish
    Pages (from-to)445-459
    Number of pages15
    JournalMolecular Endocrinology
    Issue number3
    Publication statusPublished - Mar 2015


    • Animals
    • Bradykinin
    • Cell Line
    • Epidermal Growth Factor
    • Extracellular Signal-Regulated MAP Kinases
    • Genes, Reporter
    • Humans
    • Hypothalamus
    • Interferon-gamma
    • Ligands
    • Melanocyte-Stimulating Hormones
    • Mice
    • Neurons
    • Neuropeptide Y
    • Phosphorylation
    • Phosphoserine
    • Phosphotyrosine
    • Promoter Regions, Genetic
    • Receptor, Epidermal Growth Factor
    • Receptors, Cytokine
    • STAT3 Transcription Factor
    • Suppressor of Cytokine Signaling Proteins
    • Thyrotropin-Releasing Hormone
    • Transcriptional Activation


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