Prominin‐1‐Radixin axis controls hepatic gluconeogenesis by regulating PKA activity

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). Synopsis Prominin‐1 in the hepatocytes interacts with radixin at the plasma membrane and regulates hepatic gluconeogenesis by augmenting PKA signaling via radixin as a PKA‐anchoring protein. The transmembrane protein Prominin‐1 is expressed in hepatocytes as well as cholangiocytes in the liver. Prominin‐1 functions as an anchor for radixin, which brings PKA holoenzyme to membrane microdomains, where local cAMP concentration is increased by glucagon‐induced activation of adenylyl cyclase. Prom1 knockout and knockdown result in inhibition of glucagon‐elicited CREB phosphorylation and gluconeogenesis in hepatocytes and livers. Graphical Abstract Prominin‐1 in the hepatocytes interacts with radixin at the plasma membrane and regulates hepatic gluconeogenesis by augmenting PKA signaling via radixin as a PKA‐anchoring protein.