Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, 110067, India.
Mol Cell Biochem. 2019 Nov;461(1-2):127-139. doi: 10.1007/s11010-019-03596-7. Epub 2019 Jul 27.
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.
组成型雄烷受体（CAR）是一种异生物质核受体，已知其可调节参与药物代谢、能量稳态维持和细胞增殖等关键生理过程的基因。由于该受体发挥着多种调节作用，因此了解决定 CAR 功能动态的精确细胞信号至关重要。为了探索调节 CAR 的 hitherto 未知的调控途径，我们对 CAR 蛋白序列进行了激酶预测工具分析，并鉴定出几种可识别 CAR 为底物的激酶。通过荧光活细胞成像和特定抑制剂观察到，CAR 的功能受丝裂原活化蛋白激酶（MAPK）和糖原合成酶激酶 3（GSK3）信号级联的调节。此外，胰岛素样生长因子 1（IGF1）介导的 GSK3 抑制也诱导了 CAR 的核易位，将 CAR 与 Akt 信号通路联系起来。CAR 的 T38 残基作为 GSK3 靶位的鉴定进一步证实了我们的观察结果。根据这些发现，我们提出了一个假设模型，阐述了 Akt 途径参与的 GSK3 介导的 CAR 动力学调节。进一步研究这一领域有望为 2 型糖尿病和肝细胞癌等疾病提供新的治疗靶点。
