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 beta-arrestin-mediated ERK activation

Mol Endocrinol. 2006 Nov;20(11):3014-26. doi: 10.1210/me.2006-0098. Epub 2006 Aug 3.


Classically, the FSH receptor (FSH-R) mediates its effects through coupling to guanine nucleotide-binding protein alpha S subunit (Galpha(s)) and activation of the cAMP/protein kinase A (PKA) signaling pathway. beta-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 Galpha(s)/PKA and beta-arrestins. Galpha(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 beta-arrestins. beta-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 beta-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 beta-arrestin-dependent pathway was increased. G protein-coupled receptor kinase 5 (GRK5) and GRK6 were required for beta-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 beta-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 beta-arrestin recruitment, positively regulated both desensitization and internalization but negatively regulated beta-arrestin-dependent ERK activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Arrestins / metabolism*
  • Cells, Cultured
  • Endocytosis
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • G-Protein-Coupled Receptor Kinase 2
  • Humans
  • Molecular Sequence Data
  • Mutant Proteins / metabolism
  • Phosphorylation
  • Protein Binding
  • Protein Interaction Mapping
  • Protein Structure, Tertiary
  • Protein Transport
  • Receptors, FSH / chemistry
  • Receptors, FSH / metabolism*
  • Sequence Homology, Amino Acid
  • Serine / metabolism
  • Signal Transduction
  • Threonine / metabolism
  • beta-Adrenergic Receptor Kinases / metabolism
  • beta-Arrestin 1
  • beta-Arrestins


  • ARRB1 protein, human
  • Arrestins
  • Mutant Proteins
  • Receptors, FSH
  • beta-Arrestin 1
  • beta-Arrestins
  • Threonine
  • Serine
  • GRK2 protein, human
  • beta-Adrenergic Receptor Kinases
  • G-Protein-Coupled Receptor Kinase 2
  • Extracellular Signal-Regulated MAP Kinases