title: Negative cross-talk between calcium-sensing receptor and β-catenin signaling systems in colonic epithelium.
abstract: Here, we examined the role of the extracellular Ca(2+)-sensing receptor (CaSR) in the control of colonic epithelial cell proliferation in vivo and changes in β-catenin triggered by CaSR stimulation in human colonic epithelial cells in vitro. The in vivo studies, using a novel Casr intestinal-specific knock-out mouse, indicate that the genetic ablation of the Casr leads to hyperproliferation of colonic epithelial cells, expansion of the proliferative zone, changes in crypt structure, and enhanced β-catenin nuclear localization. The in vitro results indicate that stimulation of the CaSR, by Ca(2+) or by the calcimimetic R-568, produced a striking and time-dependent decrease in the phosphorylation of β-catenin at Ser-552 and Ser-675, two amino acid residues that promote β-catenin transcriptional activity. The reduced phosphorylation of β-catenin coincided with a decline in its nuclear localization and a marked redistribution to the plasma membrane. Furthermore, CaSR stimulation promoted a down-regulation of β-catenin-mediated transcriptional activation. These studies demonstrate that signaling pathways emanating from the CaSR control colonic epithelial cell proliferation in vivo and suggest that the mechanism involves regulation of β-catenin phosphorylation.
authors.affiliation: Unit of Signal Transduction and Gastrointestinal Cancer, Division of Digestive Diseases, Department of Medicine, CURE: Digestive Diseases Research Center, David Geffen School of Medicine, UCLA, Los Angeles, California 90095, USA. orey@mednet.ucla.edu
authors.forename: Osvaldo
authors.initials: O
authors.lastname: Rey
authors.forename: Wenhan
authors.initials: W
authors.lastname: Chang
authors.forename: Daniel
authors.initials: D
authors.lastname: Bikle
authors.forename: Nora
authors.initials: N
authors.lastname: Rozengurt
authors.forename: Steven H
authors.initials: SH
authors.lastname: Young
authors.forename: Enrique
authors.initials: E
authors.lastname: Rozengurt
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology; D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D003106:Colon / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010627:Phenethylamines; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011437:Propylamines; D044169:Receptors, Calcium-Sensing / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D000814:Aniline Compounds; C095550:CASR protein, human; C107873:N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine; D010627:Phenethylamines; D011437:Propylamines; D044169:Receptors, Calcium-Sensing; D051176:beta Catenin; D002118:Calcium
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