Koo, S.-H. | Search bioRxiv

bioRxiv2022

Central role of Prominin-1 in lipid rafts during liver regeneration

Prominin-1 (PROM1), a lipid raft protein, is required for maintaining cancer stem cell properties in hepatocarcinoma cell lines, but its physiological roles in the liver have not been well studied. Here, we investigated the role of PROM1 in lipid rafts with a precise molecular mechanism during liver regeneration. We found that the expression of PROM1 increased during liver regeneration after 2/3 partial hepatectomy (PHx) or CCl4 injection. Interestingly, hepatocyte proliferation and liver regeneration were attenuated in liver-specific Prom1 knockout (Prom1LKO) mice compared to wild-type (Prom1f/f) mice. Detailed mechanistic studies revealed that PROM1 interacted with the interleukin-6 signal transducer glycoprotein 130 (GP130) and confined GP130 to lipid rafts so that STAT3 signaling by IL-6 was effectively activated. Moreover, the overexpression of the glycosylphosphatidylinsositol (GPI)-anchored first extracellular domain of PROM1 (PROM1GPI-EX1), which is a domain that binds to GP130, rescued the proliferation of hepatocytes and liver regeneration in Prom1LKO mice. PROM1 is upregulated in hepatocytes during liver regeneration, and upregulated PROM1 recruits GP130 into lipid rafts and activates the IL6-GP130-STAT3 axis. Thus, we conclude that PROM1 plays an important role in lipid rafts during liver regeneration and might be a promising target for therapeutic applications of liver transplantation.

cell biology↗

bioRxiv2019

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 Prom1+/+ and Prom1-/- mouse hepatocytes using RNA-sequencing (RNA-seq) data, and found that CREB target genes were down-regulated. This initial observation led us to determine that the 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, the 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).

cell biology↗