Work

A Dual-compartment Scaffolding Role for Receptor for Activate C Kinase 1 in Hepatic Glucagon Signaling and Gluconeogenesis

Year: 2025

Type: article

Abstract: BACKGROUND & AIMS: The hepatic glucagon-protein kinase A (PKA)-cAMP response element-binding protein (CREB) signaling axis plays a central role in regulating gluconeogenesis and maintaining glucose homeostasis during fasting. However, the mechanisms that govern the spatial coordination and substrate specificity of this pathway remain incompletely understood. This study determines the role of the scaffolding protein RACK1 (Receptor for Activated C Kinase 1) in orchestrating glucagon signaling to regulate hepatic gluconeogenesis. METHODS: ). RESULTS: expression. Overexpression of RACK1 WD1-2 and WD3-4 domains, which mediate PKA, GCGR, and CREB interactions, similarly disrupted PKA signaling and gluconeogenesis. CONCLUSIONS: RACK1 functions as a dual-compartment scaffold, assembling GCGR-PKA at the plasma membrane and PKAcα-CREB in the nucleus, enabling precise glucagon signaling and gluconeogenesis while sparing insulin pathways, thereby ensuring compartmentalized regulation of hepatic glucose homeostasis.

Source: Cellular and Molecular Gastroenterology and Hepatology

DOI: 10.1016/j.jcmgh.2025.101666

Authors: Cancan Lyu, Ling Yang, Songhai Chen

Institution: University of Iowa

Language: English

Topic: Metabolism, Diabetes, and Cancer

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: gold

Estimated APC paid: $3,430

Funders: University of Iowa, National Institutes of Health, National Cancer Institute