Stress pathway activation induces phosphorylation of retinoid X receptor.
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.
Lee
H Y
HY
Department of Thoracic/Head and Neck Medical Oncology, Clinical Cancer Prevention, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Suh
Y A
YA
Robinson
M J
MJ
Clifford
J L
JL
Hong
W K
WK
Woodgett
J R
JR
Cobb
M H
MH
Mangelsdorf
D J
DJ
Kurie
J M
JM
D000818:Animals; D019556:COS Cells; D004789:Enzyme Activation; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter / Q000235:genetics; D048031:JNK Mitogen-Activated Protein Kinases; D007797:Laminin / Q000235:genetics; D008024:Ligands; D048670:MAP Kinase Kinase 4; D051379:Mice; D048055:Mitogen-Activated Protein Kinase 8; D048056:Mitogen-Activated Protein Kinase 9; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D018168:Receptors, Retinoic Acid / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D047488:Retinoid X Receptors; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014212:Tretinoin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism
D007797:Laminin; D008024:Ligands; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D014443:Tyrosine; D014212:Tretinoin; D048056:Mitogen-Activated Protein Kinase 9; D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; C482562:Map2k4 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases