Visit our Expo - Redox and Inflammation signaling 2012

Session III : Protein kinase cascades as therapeutic targets Poster III, 29
Multiple roles for beta-arrestins in FSH signalling : a 5 S/T cluster in the C-terminus of
the receptor is important for beta-arrestin recruitment, desensitization and
internalization but not for beta-arrestin-mediated Erk activation.
E. Kara, P. Crepieux, C. Gauthier, N. Martinat, V. Piketty, F. Guillou, E. Reiter
UMR INRA-CNRS-Univ. Tours-Haras Nationaux, PRC, Equipe " Mécanismes d’action
des Gonadotropines ", 37380 Nouzilly France
The follicle-stimulating hormone receptor (FSH-R) is a seven transmembrane spanning
receptor that couples to G"s upon agonist stimulation. #-arrestins (#-arr) are rapidly recruited
to the FSH-activated receptor and play key roles in the desensitization and internalization
processes. In addition, #-arr are able to activate the ERK pathway through a G proteinindependent
mechanism.
We have identified a cluster of five Ser/Thr residues in the c-terminus of the FSH-R (T638,
T640, S641, S642 and T644) which is important for #-arr recruitment. When these residues
were mutated into Alanines (5A), the FSH-induced recruitment of #-arr 1 and #-arr 2 was
reduced by 90% as assessed by co-immunoprecipitation with the FLAG-receptor. As
expected, cAMP accumulation by the 5A mutant was enhanced when compared to the wildtype
receptor. Consistantly, internalization of the 5A mutant was reduced when compared to
the wild-type control. In striking contrast however, the ability of the 5A mutant to activate
ERK via the #-arr pathway was actually increased when compared to the wild-type receptor.
Together, these results suggest that at least two functionally distinct pools of #-arr are
recruited to the activated FSH-R : 1) the predominant part interacts with the Ser638-Thr644
cluster, involved in both desensitization and internalization and exerts a negative role on the
ERK activation by both Gs and #-arr-dependent mechanisms, 2) a smaller proportion of the
#-arr does not interact with the Ser/Thr cluster and is required for ERK activation through a
#-arr-dependent pathway.
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