title: Calcium-sensing receptor inhibits TGF-β-signaling by decreasing Smad2 phosphorylation.
abstract: 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.
authors.affiliation: Department of Cell Biology, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Apartado postal 14-740, México, D.F. 07000, Mexico.
authors.forename: Diana
authors.initials: D
authors.lastname: Organista-Juárez
authors.forename: Jorge
authors.initials: J
authors.lastname: Carretero-Ortega
authors.forename: Onasis
authors.initials: O
authors.lastname: Vicente-Fermín
authors.forename: Genaro
authors.initials: G
authors.lastname: Vázquez-Victorio
authors.forename: Marcela
authors.initials: M
authors.lastname: Sosa-Garrocho
authors.forename: José
authors.initials: J
authors.lastname: Vázquez-Prado
authors.forename: Marina
authors.initials: M
authors.lastname: Macías-Silva
authors.forename: Guadalupe
authors.initials: G
authors.lastname: Reyes-Cruz
mesh_terms: D000818:Animals; D057809:HEK293 Cells; D006801:Humans; D044162:Parathyroid Hormone-Related Protein / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D059748:Proteolysis; D051381:Rats; D044169:Receptors, Calcium-Sensing / Q000378:metabolism*; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000502:physiology*
chemical_list: D044162:Parathyroid Hormone-Related Protein; D044169:Receptors, Calcium-Sensing; D051899:Smad2 Protein; C497784:Smad2 protein, rat; C508962:Tgfb1 protein, rat; D053773:Transforming Growth Factor beta1; C473605:extracellular calcium cation-sensing receptor, rat; D046988:Proteasome Endopeptidase Complex
keywords: GPCR; Smad; TGF-β; cell signaling; calcium sensing receptor; trafficking