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 α and retinoid X receptor α in yeast. Although VDR-PP1c and VDR-PP2Ac interaction is ligand-independent in vivo, 1α,25-dihydroxy-vitamin D3 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 (p70S6k). Finally, we demonstrate that the endogenous VDR, PP1c or PP2Ac, and p70S6k are present in a ternary complex in vivo, and the interaction of p70S6k with the VDR-PP complex is modulated by the phosphorylation state of the kinase. Since p70S6k is essential for G1-S transition, our results provide a molecular basis of 1α,25-dihydroxyvitamin D3-induced G1 block in colon cancer cells.