Stress Pathway Activation Induces Phosphorylation of Retinoid X Receptor

作者：Ho‐Young Lee, Young‐Ah Suh, Megan J. Robinson, John L. Clifford, Waun Ki Hong, James Robert Woodgett, Melanie H. Cobb, David J. Mangelsdorf, Jonathan M. Kurie · 发表于：Journal of Biological Chemistry · 年份：2000 · DOI：10.1074/jbc.m005490200 · 被引用次数：91 · 研究领域：Retinoids in leukemia and cellular processes、Estrogen and related hormone effects、interferon and immune responses

Cellular stresses inhibit retinoid signaling, but the molecular basis for this phenomenon has not been revealed. Here, we present evidence that retinoid X receptor (RXR) is a substrate for both mitogen-activated protein kinase kinase-4 (MKK4/SEK1) and its downstream mediator c-Jun N-terminal kinase (JNK). MKK4/SEK1 and JNK recognized distinct features on RXR in the DE and AB regions, respectively. Phosphorylation by MKK4/SEK1 had profound effects on the biochemical properties of RXR, inhibiting the expression of genes activated by RXR-retinoic acid receptor complexes. Tyr-249 in the RXR DE region was required for the inhibitory effect of MKK4/SEK1. These effects were significantly reduced in MKK4/SEK1-null cells, indicating that MKK4/SEK1 is required for the suppression of retinoid signaling by stress. Findings presented here demonstrate that MKK4/SEK1 can directly modulate transcription by phosphorylating RXR, a novel MKK4/SEK1 substrate.