Signaling control of the constitutive androstane receptor (CAR)

Abstract

The constitutive androstane receptor (CAR, NR1I3) plays a crucial role in the regulation of drug metabolism, energy homeostasis, and cancer development through modulating the transcription of its numerous target genes. Different from prototypical nuclear receptors, CAR can be activated by either direct ligand binding or ligand-independent (indirect) mechanisms both initiated with nuclear translocation of CAR from the cytoplasm. In comparison to the well-defined ligand-based activation, indirect activation of CAR appears to be exclusively involved in the nuclear translocation through mechanisms yet to be fully understood. Accumulating evidence reveals that without activation, CAR forms a protein complex in the cytoplasm where it can be functionally affected by multiple signaling pathways. In this review, we discuss recent progresses in our understanding of the signaling regulation of CAR nuclear accumulation and activation. We expect that this review will also provide greater insight into the similarity and difference between the mechanisms of direct vs. indirect human CAR activation.

Figure 1

Schematic illustration of biological functions of CAR. The size of hollow arrows indicates the abundance of available evidence for each function of CAR. Up and down black arrows symbolize increased and decreased gene expression, respectively

Figure 2

Antagonistic effect of phenobarbital on EGFR signaling and CAR activation. Arrows indicate activation and the blunt arrow represents deactivation. (This figure was adopted from Mutoh et al., , Science Signaling)

Figure 3

Signaling control of CAR activation. Chemicals illustrating activation or deactivation of a signaling pathway are denoted in blue and red, respectively