title: A vitamin D receptor-Ser/Thr phosphatase-p70 S6 kinase complex and modulation of its enzymatic activities by the ligand.
abstract: We provide evidence of a cross-talk between nuclear receptor and Ser/Thr protein phosphatases and show that vitamin D receptor (VDR) interacts with the catalytic subunit of protein phosphatases, PP1c and PP2Ac, and induces their enzymatic activity in a ligand-dependent manner. PP1c specifically interacts with VDR but not retinoic acid receptor alpha and retinoid X receptor alpha in yeast. Although VDR-PP1c and VDR-PP2Ac interaction is ligand-independent in vivo, 1alpha,25-dihydroxy-vitamin D(3) induces VDR-associated phosphatase activity. Further, VDR modulation of PP1c/PP2Ac activity results in a rapid and specific dephosphorylation and inactivation of their substrate, p70 S6 kinase (p70(S6k)). Finally, we demonstrate that the endogenous VDR, PP1c or PP2Ac, and p70(S6k) are present in a ternary complex in vivo, and the interaction of p70(S6k) with the VDR-PP complex is modulated by the phosphorylation state of the kinase. Since p70(S6k) is essential for G(1)-S transition, our results provide a molecular basis of 1alpha,25-dihydroxyvitamin D(3)-induced G(1) block in colon cancer cells.
authors.affiliation: Gene Regulation, Bone, and Inflammation Research, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Bettoun
authors.forename: Donald W
authors.initials: DW
authors.lastname: Buck
authors.forename: Jianfen
authors.initials: J
authors.lastname: Lu
authors.forename: Berket
authors.initials: B
authors.lastname: Khalifa
authors.forename: William W
authors.initials: WW
authors.lastname: Chin
authors.forename: Sunil
authors.initials: S
authors.lastname: Nagpal
mesh_terms: D016193:G1 Phase; D006801:Humans; D008024:Ligands; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation; D054645:Protein Phosphatase 1; D018167:Receptors, Calcitriol / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D008024:Ligands; D018167:Receptors, Calcitriol; D019893:Ribosomal Protein S6 Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1