title: Activation of the MAP kinase cascade by exogenous calcium-sensing receptor.
abstract: In Rat-1 fibroblasts and ovarian surface epithelial cells, extracellular calcium induces a proliferative response which appears to be mediated by the G-protein coupled calcium-sensing receptor (CaR), as expression of the nonfunctional CaR-R795W mutant inhibits both thymidine incorporation and activation of the extracellular-regulated kinase (ERK) in response to calcium. In this report we utilized CaR-transfected HEK293 cells to demonstrate that functional CaR is necessary and sufficient for calcium-induced ERK activation. CaR-dependent ERK activation was blocked by co-expression of the Ras dominant-negative mutant, Ras N17, and by exposure to the phosphatidyl inositol 3' kinase inhibitors wortmannin and LY294002. In contrast to Rat-1 fibroblasts, CaR-mediated in vitro kinase activity of ERK2 was unaffected by tyrosine kinase inhibitor herbimycin in CaR-transfected HEK293 cells. These results suggest that usage of distinct pathways downstream of the CaR varies in a cell-type specific manner, suggesting a potential mechanism by which activation of the CaR could couple to distinct calcium-dependent responses.
authors.affiliation: Department of Cell and Developmental Biology, Oregon Health Sciences University, Portland 97201-3098, USA.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Hobson
authors.forename: Jay
authors.initials: J
authors.lastname: Wright
authors.forename: Fred
authors.initials: F
authors.lastname: Lee
authors.forename: Scott E
authors.initials: SE
authors.lastname: McNeil
authors.forename: Timothy
authors.initials: T
authors.lastname: Bilderback
authors.forename: Karin D
authors.initials: KD
authors.lastname: Rodland
mesh_terms: D000818:Animals; D016227:Benzoquinones; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000201:enzymology; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D005822:Genetic Vectors / Q000235:genetics; D047029:Lactams, Macrocyclic; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010957:Plasmids / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011809:Quinones / Q000494:pharmacology; D051381:Rats; D044169:Receptors, Calcium-Sensing / Q000235:genetics / Q000502:physiology*; D017828:Rifabutin / Q000031:analogs & derivatives; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D016227:Benzoquinones; D047029:Lactams, Macrocyclic; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D011809:Quinones; D044169:Receptors, Calcium-Sensing; D017828:Rifabutin; D018631:ras Proteins; C020754:herbimycin