title: Old dance with a new partner: EGF receptor as the phenobarbital receptor mediating Cyp2B expression.
abstract: The decades-long quest for the phenobarbital (PhB) receptor that mediates activation of Cyp2B would appear fulfilled with the discovery by Mutoh et al., who found that PhB binds with pharmacological affinity to the epidermal growth factor receptor (EGFR). This finding provides a molecular basis for the suppression of hepatocyte EGFR signaling observed with PhB treatment, as previously noted in the context of tumor promotion. Although the PhB-mediated induction of Cyp2B expression through the association of a canonical nuclear receptor with the 5'-enhancer PBREM of Cyp2B is well known, direct binding of PhB to constitutive active androstane receptor (CAR, also known as NR1I3) typical of other xenobiotic-activated nuclear receptors has eluded detection. One EGF-activated pathway affected by the PhB-EGFR interaction is the loss of tyrosine phosphorylation of the scaffold protein RACK1. Dephosphorylated RACK1 provides the mechanistic link between the binding of PhB to EGFR and its effects on CAR by facilitating the interaction of serine/threonine phosphatase PP2A with inactive phosphorylated CAR. The dephosphorylation of CAR enables its translocation to the nucleus and activation of Cyp2B expression. Because EGFR and transducers RACK1, PP2A, and other partners are highly networked in numerous cellular pathways, this newly discovered partnership will surely reveal new fundamental roles for PhB beyond the regulation of drug metabolism.
authors: Department of Toxicology, College of Pharmacy, University of Louisiana, Monroe, LA 71201, USA. meyer@ulm.edu
authors: Sharon A
authors: SA
authors: Meyer
authors: Randy L
authors: RL
authors: Jirtle
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D000090702:Constitutive Androstane Receptor; D000072467:Cytochrome P450 Family 2; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D018757:GABA Modulators / Q000378:metabolism / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D008954:Models, Biological; D010634:Phenobarbital / Q000378:metabolism / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D000091402:Prohibitins; D011485:Protein Binding / Q000187:drug effects; D054648:Protein Phosphatase 2 / Q000378:metabolism; D051381:Rats; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000090702:Constitutive Androstane Receptor; D018757:GABA Modulators; C000716327:NR1I3 protein, human; C000716328:Nr1i3 protein, mouse; C000716329:Nr1i3 protein, rat; C000717328:PHB protein, human; C000717332:Phb protein, rat; D000091402:Prohibitins; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D011963:Receptors, GABA-A; C030975:barbiturate receptor; D004815:Epidermal Growth Factor; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C101679:Cyp2b10 protein, mouse; D000072467:Cytochrome P450 Family 2; D066246:ErbB Receptors; D054648:Protein Phosphatase 2; D010634:Phenobarbital