Tunneling Nanotube Research Center, Korea University, Seoul, Korea.
Division of Life Sciences, Korea University, Seoul, Korea.
EMBO Rep. 2020 Nov 5;21(11):e49416. doi: 10.15252/embr.201949416. Epub 2020 Oct 8.
Prominin-1 (Prom1) is a major cell surface marker of cancer stem cells, but its physiological functions in the liver have not been elucidated. We analyzed the levels of mRNA transcripts in serum-starved primary WT (Prom1 ) and KO (Prom1 ) mouse hepatocytes using RNA sequencing (RNA-seq) data, and found that CREB target genes were downregulated. This initial observation led us to determine that Prom1 deficiency inhibited cAMP response element-binding protein (CREB) activation and gluconeogenesis, but not cyclic AMP (cAMP) accumulation, in glucagon-, epinephrine-, or forskolin-treated liver tissues and primary hepatocytes, and mitigated glucagon-induced hyperglycemia. Because Prom1 interacted with radixin, Prom1 deficiency prevented radixin from localizing to the plasma membrane. Moreover, systemic adenoviral knockdown of radixin inhibited CREB activation and gluconeogenesis in glucagon-treated liver tissues and primary hepatocytes, and mitigated glucagon-elicited hyperglycemia. Based on these results, we conclude that Prom1 regulates hepatic PKA signaling via radixin functioning as an A kinase-anchored protein (AKAP).
Prominin-1（Prom1）是癌症干细胞的主要细胞表面标志物，但它在肝脏中的生理功能尚未阐明。我们使用 RNA 测序（RNA-seq）数据分析了饥饿培养的 WT（Prom1）和 KO（Prom1）小鼠原代肝细胞中的 mRNA 转录本水平，发现 CREB 靶基因下调。这一初步观察结果促使我们确定 Prom1 缺失抑制了 cAMP 反应元件结合蛋白（CREB）的激活和胰高血糖素、肾上腺素或 forskolin处理的肝组织和原代肝细胞中的糖异生，但不影响 cAMP 的积累，并减轻了胰高血糖素引起的高血糖。因为 Prom1 与根蛋白相互作用，所以 Prom1 缺失阻止了根蛋白向质膜的定位。此外，全身性腺病毒敲低根蛋白抑制了胰高血糖素处理的肝组织和原代肝细胞中的 CREB 激活和糖异生，并减轻了胰高血糖素引起的高血糖。基于这些结果，我们得出结论，Prom1 通过根蛋白作为蛋白激酶 A 锚定蛋白（AKAP）发挥作用来调节肝 PKA 信号。
