HUMAN VITAMIN-D-RECEPTOR PHOSPHORYLATION BY CASEIN KINASE-II AT SER-208 POTENTIATES TRANSCRIPTIONAL ACTIVATION

The potential functional significance of human 1,25-dihydroxyvitamin D -3 [1,25(OH)(2)D-3] receptor (hVDR) phosphorylation at Ser-208 was eva luated by cotransfecting COS-7 kidney cells with hVDR constructs and t he catalytic subunit of human casein kinase II (CK-II), Under these co nditions, hVDR is intensely phosphorylated in a reaction that depends on both CK-II and the presence of Ser-208. The resulting hyperphosphor ylated receptor is unaltered in its kinetics for binding the 1,25(OB)( 2)D-3 ligand, its partitioning into the nucleus, and its ability to as sociate with a vitamin D responsive element, Replacement of Ser-208 wi th glycine or alanine indicates that phosphorylation of hVDR at Ser-20 8 is not obligatory for 1,25(OH)(2)D-3 action, but coexpression of wil d-type hVDR and CK-II elicits a dose-dependent enhancement of 1,25(OH) (2)D-3-stimulated transcription of a vitamin D responsive element repo rter construct, This enhancement by CK-II is abolished by mutating Ser -208 to glycine or alanine and does not occur with glucocorticoid rece ptor-mediated transcription, Therefore, phosphorylation of hVDR by CK- II at Ser-208 specifically modulates its transcriptional capacity, sug gesting that this covalent modification alters the conformation of VDR to potentiate its interaction with the machinery for DNA transcriptio n.