Mitogen-activated protein kinase inhibits 1,25-dihydroxyvitamin D-3-dependent signal transduction by phosphorylating human retinoid X receptor alpha

Human retinoid X receptor alpha (hRXR alpha) is a member of the nuclear rec eptor family of transcriptional regulators. It regulates transcription thro ugh its association with several heterodimeric partners, including the vita min D-3 receptor (VDR). Signaling through the VDR is essential for normal c alcium homeostasis and has been shown to inhibit the proliferation of cance r cells derived from a number of tissues. Here we show that phosphorylation of hRXR alpha in ras-transformed human keratinocytes through the activated Ras-Raf-mitogen-activated protein kinase (Ras Raf-MAP kinase) pathway resu lts in attenuated transactivation by the VDR and resistance to the growth i nhibitory action of 1,25 dihydroxyvitamin D-3 [1,25(OH)(2)D-3] and RXR-spec ific agonist LG1069 (4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naph- talenyl) ethenyl]-benzoic acid). Phosphorylation of hRXR alpha occurs at s erine 260, a consensus MAP kinase site. Inhibition of MAP kinase activity o r point mutagenesis of serine 260 of hRXR alpha reverses the observed resis tance to 1,25(OH)(2)D-3 and LG1069. Thus, hRXR alpha is a downstream target of MAP kinase, and its phosphorylation may play an important role in malig nant transformation.