Endocrine Abstracts

An intriguing connection between classical GPCR signalling and the regulation of β-catenin activity has emerged in recent years. To date, the FP_B prostanoid, lysophosphatidic acid, M1 muscarinic acetylcholine, and thromboxane A2/TP_α GPCRs have been demonstrated to target β-catenin transcriptional activity. β-catenin has a well-established role as a key effector of the canonical Wnt/β-catenin signalling pathway, where it acts as a co-factor with TCF/LEF to mediate transcription of Wnt target genes. In recent studies, we have shown that the GnRH receptor can target several elements of canonical Wnt/β-catenin signalling, including inhibition of GSK-3, stabilisation and nuclear accumulation of β-catenin, regulation of β-catenin/TCF-dependent transcription, and up-regulation of several Wnt/β-catenin target genes. Other mediators of the Wnt/β-catenin pathway were implicated including CK1 and TCF, as well as several mediators of classical GnRH receptor signal transduction including G_q, PLC-β, and PKC-δ. In addition to canonical Wnt/β-catenin signalling, several non-canonical Wnt-activated β-catenin-independent pathways have been proposed, including the Wnt/Ca²⁺ pathway, which has been suggested to target a degree of NFAT-dependent transcriptional activity, although reports are conflicting. We have shown that GnRH can target NFAT-dependent transcriptional activity. This was dependent on G_q, Ca²⁺, PKC, and calcineurin. Intriguingly, GnRH-induced NFAT activity, and the up-regulation of several NFAT target genes, was shown to be both PKC-δ- and TCF-dependent, thereby implying a dual role for PKC-δ and TCF in targeting both β-catenin and calcineurin/NFAT signalling in response to GnRH. These studies highlight a potential cross-talk between GnRH and Wnt signalling pathways. Furthermore, the implication of TCF in NFAT-dependent transcriptional activity is suggestive of a hitherto unrecognised level of cross-talk between the canonical Wnt/β-catenin and calcineurin/NFAT signalling pathways.