Calcium-sensing receptor inhibits TGF-β-signaling by decreasing Smad2 phosphorylation.

Calcium-sensing receptor (CaSR) contributes to maintain homeostatic levels of extracellular calcium. In addition, CaSR controls other cellular activities such as proliferation and migration, particularly in cells not related to extracellular calcium homeostasis, potentially by cross-talking with parallel signaling pathways. Here we report that CaSR attenuates transforming growth factor-β (TGF-β)-signaling in hepatic C9 cells and in transfected HEK293 cells. Wild type CaSR interferes with TGF-β-dependent Smad2 phosphorylation and induces its proteasomal degradation, resulting in a decrease of TGF-β-dependent transcriptional activity, whereas an inactivating CaSR mutant does not transduce an inhibitory effect of extracellular calcium on TGF-β signaling. Attenuation of TGF-β signaling in response to extracellular calcium is linked to Rab11-dependent CaSR-trafficking with the intervention of CaSR carboxyl-terminal tail. Our data suggest that CaSR might regulate TGF-β-dependent cellular responses mediated by TGF-β signaling inhibition.