Influence of signaling kinases on functional dynamics of nuclear receptor CAR
Constitutive androstane receptor (CAR) is a xenobiotic nuclear receptor known to regulate genes involved in key physiological processes like drug metabolism, maintenance of energy homeostasis, and cell proliferation. Owing to the diverse regulatory roles played by the receptor, it is critical to understand the precise cellular signals that dictate functional dynamics of CAR. With the objective of exploring the hitherto unknown regulatory pathways modulating CAR, we subjected the CAR protein sequence to a kinase prediction tool and identified several kinases recognizing CAR as a substrate. Using fluorescence live cell imaging and specific inhibitors it was observed that CAR functions under the regulation of mitogen-activated protein kinase (MAPK) and glycogen synthase kinase 3 (GSK3) signaling cascade. Additionally, insulin-like growth factor 1 (IGF1)-mediated inhibition of GSK3 also induced nuclear translocation of CAR linking CAR to the Akt signaling pathway. Identification of T38 residue of CAR as the GSK3 target site further substantiated our observations. Taking cues from these findings, we propose a hypothetical model elucidating the GSK3-mediated regulation of CAR dynamics through the involvement of Akt pathway. Further research into this area is expected to provide novel therapeutic targets in disease conditions like type 2 diabetes and hepatocellular carcinoma.
KeywordsConstitutive androstane receptor Nuclear receptor Signaling kinase Glycogen synthase kinase 3 Akt
The research work presented herein was financially supported by a research grant to RKT by National Agricultural Science Fund - Indian Council of Agricultural Research (F.No.NASF/ABA-7006/2018–2019) and University with Potential for Excellence - II (ID 25). Financial assistance to our Centre by Department of Science and Technology - Promotion of University Research and Scientific Excellence and University Grants Commission - Special Assistance Programme is duly acknowledged. Doctoral research fellowship to ASY by University Grants Commission - Jawaharlal Nehru University is acknowledged. We apologize to those of our colleagues whose significant contributions in the subject of this manuscript are not cited due to limited space.
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Conflict of interest
The authors declare that they have no conflict of interest.
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