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Nuclear Stabilization of β-Catenin and Inactivation of Glycogen Synthase Kinase-3β by Gonadotropin-Releasing Hormone: Targeting Wnt Signaling in the Pituitary Gonadotrope

Medical Research Council Human Reproductive Sciences Unit, The Queen’s Medical Research Institute, Edinburgh EH16 4TJ, Scotland, United Kingdom

Address all correspondence and requests for reprints to: Adam J. Pawson, Medical Research Council Human Reproductive Sciences Unit, The Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, Scotland, United Kingdom. E-mail: a.pawson{at}hrsu.mrc.ac.uk.

The GnRH receptor is a G protein-coupled receptor (GPCR), and its ligand GnRH is the central regulator of the reproductive system. GnRH receptors are known to target a wide variety of signal transduction pathways. Several recent studies have shown that activation of GPCRs can impact on β-catenin signaling. β-Catenin is the main effecter of the Wnt signaling pathway where it acts with the transcription factors T cell factor/lymphoid enhancer factor to mediate the transcription of Wnt target genes. We show that GnRH treatment promotes the nuclear accumulation of β-catenin, activation of T cell factor-dependent transcription, and up-regulation of Wnt target genes, c-Jun, Fra-1, and c-Myc. These results are observed in human embryonic kidney 293/GnRH receptor-expressing cells and have been recapitulated in LβT2 and T3-1 mouse gonadotrope cells. In addition to these findings, we show that GnRH treatment mediates the inactivation of glycogen synthase kinase-3, a protein serine/threonine kinase that regulates β-catenin degradation within the Wnt signaling pathway. Our findings extend the number of GPCRs that can target β-catenin signaling through diverse pathways. Furthermore, this is the first demonstration of the targeting of Wnt/β-catenin signaling by a peptide hormone GPCR.

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