Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 286, Issue 41, Pages 35763-35769Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M111.284596
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- National Institutes of Health
- National Institutes of Health, NIEHS [Z01ES1005-01]
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The nuclear constitutive active/androstane receptor (CAR) is inactivated and sequestered in the cytoplasm when Thr-38 is phosphorylated. Here, we have demonstrated that activated ERK1/2 interacts with phosphorylated CAR to repress dephosphorylation of Thr-38. The phosphorylation-dependent interaction between CAR and ERK1/2 was examined by co-immunoprecipitation experiments of ectopically expressed FLAG-tagged CAR T38A and CAR T38D mutants with endogenous phospho-ERK1/2 in Huh-7 cells. Phospho-ERK1/2 coprecipitated only the phosphorylation-mimicking CAR T38D mutant; this coprecipitation was mediated by the interaction with the xenochemical response signal peptide near the C terminus of CAR. This interaction increased after EGF treatment and decreased after treatment with the MEK inhibitor U0126 as well as after knockdown of MEK1/2 by shRNA in Huh-7 cells. The phosphorylation levels of Thr-38 of CAR decreased in U0126-treated Huh-7 cells. Thus, activated ERK1/2 interacts with CAR and represses dephosphorylation of Thr-38, providing a cell signal-regulated mechanism for CAR activation.
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