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A Phosphorylation Cluster of Five Serine and Threonine Residues in the C-Terminus of the Follicle-Stimulating Hormone Receptor Is Important for Desensitization But Not for ß-Arrestin-Mediated ERK Activation

Institut National de la Recherche Agronomique, Unité Mixte de Recherche 6175 Institut National de la Recherche Agronomique/Centre National de Recherche Scientifique/Université de Tours/Haras Nationaux/Institut Fédératif de Recherche 135, 37380 Nouzilly, France

Address all correspondence and requests for reprints to: Eric Reiter, Unité Mixte de Recherche 6175, 37380 Nouzilly, France. E-mail: reiter{at}tours.inra.fr.

Classically, the FSH receptor (FSH-R) mediates its effects through coupling to guanine nucleotide-binding protein S subunit (G_s) and activation of the cAMP/protein kinase A (PKA) signaling pathway. ß-Arrestins are rapidly recruited to the FSH-activated receptor and play key roles in its desensitization and internalization. Here, we show that the FSH-R expressed in HEK 293 cells activated ERK by two temporally distinct pathways dependent, respectively, on G_s/PKA and ß-arrestins. G_s/PKA-dependent ERK activation was rapid, transient, and blocked by H89 (a PKA inhibitor), but it was insensitive to small interfering RNA-mediated depletion of ß-arrestins. ß-Arrestin-dependent ERK activation was slower but more sustained and was insensitive to H89. We identified five Ser/Thr residues in the C terminus of the receptor (638–644) as a major phosphorylation site. Mutation of these residues into Ala (5A FSH-R) significantly reduced the stability of FSH-induced ß-arrestin 1 and 2 interaction when compared with the wild-type receptor. As expected, the 5A FSH-R-mediated cAMP accumulation was enhanced, and its internalization was reduced. In striking contrast, the ability of the 5A FSH-R to activate ERK via the ß-arrestin-dependent pathway was increased. G protein-coupled receptor kinase 5 (GRK5) and GRK6 were required for ß-arrestin-dependent ERK activation by both the wild-type and 5A FSH-R. By contrast, GRK2 depletion enhanced ERK activation by the wild-type FSH-R but not by the 5A FSH-R. In conclusion, we demonstrate the existence of a ß-arrestin-dependent, GRK-regulated mechanism for ERK activation by the FSH-R. A phosphorylation cluster in the C terminus of the FSH-R, identified as a site of ß-arrestin recruitment, positively regulated both desensitization and internalization but negatively regulated ß-arrestin-dependent ERK activation.

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