Ligand modulates VDR-Ser/Thr protein phosphatase interaction and p70S6 kinase phosphorylation in a cell-context-dependent manner.

Abstract We have recently shown that in colon cancer cells, Vitamin D receptor (VDR) interacts with the catalytic subunit of Ser/Thr protein phosphatases, PP1c and PP2Ac, and induces their enzymatic activity in a ligand-dependent manner. The VDR–PP1c and VDR–PP2Ac interactions were ligand independent in vivo, and 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 )-mediated increase in VDR-associated phosphatase activity resulted in dephosphorylation and inactivation of p70S6 kinase in colon cancer cells. Here, we demonstrate that in myeloid leukemia cells, 1,25(OH) 2 D 3 treatment increased the Thr389 phosphorylation of p70S6 kinase. Accordingly, 1,25(OH) 2 D 3 decreased VDR-associated Ser/Thr protein phosphatase activity by dissociating VDR–PP1c and VDR–PP2Ac interactions. Further, 1,25(OH) 2 D 3 increased the association between VDR and Thr389 phosphorylated p70S6 kinase. Finally, by using non-secosteroidal VDR ligands, we demonstrate a separation between transactivation and p70S6 kinase phosphorylation activities of VDR and show pharmacologically that p70S6 kinase phosphorylation correlates with HL-60 cell differentiation.