Phenobarbital Indirectly Activates the Constitutive Active Androstane Receptor (CAR) by Inhibition of Epidermal Growth Factor Receptor Signaling

Sci. Signal., 7 May 2013
Vol. 6, Issue 274, p. ra31
DOI: 10.1126/scisignal.2003705

Phenobarbital Indirectly Activates the Constitutive Active Androstane Receptor (CAR) by Inhibition of Epidermal Growth Factor Receptor Signaling

  1. Shingo Mutoh1,
  2. Mack Sobhany1,
  3. Rick Moore1,
  4. Lalith Perera2,
  5. Lee Pedersen2,3,
  6. Tatsuya Sueyoshi1, and
  7. Masahiko Negishi1,*
  1. 1Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
  2. 2Laboratory of Structural Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
  3. 3Department of Chemistry, University of North Carolina, Chapel Hill, NC 27599, USA.
  1. *Corresponding author. E-mail: negishi{at}niehs.nih.gov

Abstract

Phenobarbital is a central nervous system depressant that also indirectly activates nuclear receptor constitutive active androstane receptor (CAR), which promotes drug and energy metabolism, as well as cell growth (and death), in the liver. We found that phenobarbital activated CAR by inhibiting epidermal growth factor receptor (EGFR) signaling. Phenobarbital bound to EGFR and potently inhibited the binding of EGF, which prevented the activation of EGFR. This abrogation of EGFR signaling induced the dephosphorylation of receptor for activated C kinase 1 (RACK1) at Tyr52, which then promoted the dephosphorylation of CAR at Thr38 by the catalytic core subunit of protein phosphatase 2A. The findings demonstrated that the phenobarbital-induced mechanism of CAR dephosphorylation and activation is mediated through its direct interaction with and inhibition of EGFR.

Citation:

S. Mutoh, M. Sobhany, R. Moore, L. Perera, L. Pedersen, T. Sueyoshi, and M. Negishi, Phenobarbital Indirectly Activates the Constitutive Active Androstane Receptor (CAR) by Inhibition of Epidermal Growth Factor Receptor Signaling. Sci. Signal. 6, ra31 (2013).

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