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. Author manuscript; available in PMC: 2017 Sep 1.
Published in final edited form as: Biochim Biophys Acta. 2016 Feb 10;1859(9):1130–1140. doi: 10.1016/j.bbagrm.2016.02.006

Figure 1. Schematic Illustration of Mechanisms of CAR Activation.

Figure 1

Direct Activation – CAR is sequestered in a cytoplasmic complex containing HSP90 and CCRP. Upon ligand binding, these chaperones dissociate and CAR translocates to the nucleus where it heterodimerizes with RXR, recruits coactivators GRIP1 and SRC1, and binds to its response element to initiate gene transcription. Indirect Activation – When sequestered in the cytoplasm, the Thr38 residue of CAR is phosphorylated by PKC, and dephosphorylation of this residue for CAR activation can be inhibited by ERK1/2 upon activation of the EGFR signaling pathway. When a PB-like compound binds to the EGFR receptor and inhibits EGF-mediated signaling, RACK1 is dephosphorylated at Tyr52 and recruits PP2A to the CAR protein complex, where it dephosphorylates the Thr38 residue and induces CAR nuclear translocation and activation.