Serine-727 phosphorylation activates hypothalamic STAT-3 independently from tyrosine-705 phosphorylation
Breit A, Besik V, Solinski HJ, Muehlich S, Glas E, Yarwood SJ, Gudermann T (2015)
Publication Type: Journal article
Publication year: 2015
Journal
Book Volume: 29
Pages Range: 445-459
Journal Issue: 3
DOI: 10.1210/me.2014-1300
Abstract
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 hypo-thalamic cell lines and analyzed the effects of various hormones on STAT-3-dependent reporter gene activity and observed that IFN-7, epidermal growth factor (EGF), and bradykinin (BK) induce similar STAT-3 reporter activation. EGF and BK solely increased Ser-727 and IFN-7 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-7 and EGF on the expression of the STAT-3-dependent genes thyroliberin-releasing hormone and suppressors of cytokine signaling-3. EGF but not IFN-7 enhanced thyroliberin-releasing hormone expression via STAT-3. With regard to suppressors of cytokine signaling-3, we observed prolonged expression induced by IFN-7 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 hypo-thalamic STAT-3, but, in terms of targeted genes and required cofactors, entails distinct modes of STAT-3 actions compared with IFN-7-induced Tyr-705 phosphorylation.
Involved external institutions
United Kingdom (GB)
Germany (DE)How to cite
APA:
Breit, A., Besik, V., Solinski, H.J., Muehlich, S., Glas, E., Yarwood, S.J., & Gudermann, T. (2015). Serine-727 phosphorylation activates hypothalamic STAT-3 independently from tyrosine-705 phosphorylation. Molecular Endocrinology, 29(3), 445-459. https://doi.org/10.1210/me.2014-1300
MLA:
Breit, Andreas, et al. "Serine-727 phosphorylation activates hypothalamic STAT-3 independently from tyrosine-705 phosphorylation." Molecular Endocrinology 29.3 (2015): 445-459.
BibTeX: Download