5'-AMP-activated protein kinase–CREB-regulated transcription coactivator 2–Coat protein complex II axis (AMPK–CRTC2–COPII axis)

The AMPK–CRTC2–COPII axis is a multi-component signaling pathway that integrates cellular energy sensing with the regulation of hepatic glucose and lipid metabolism. At the center of this axis, the energy-sensing kinase AMPK (5'-AMP-activated protein kinase) phosphorylates the transcriptional coactivator CRTC2 (CREB-regulated transcription coactivator 2) at specific residues, such as Ser171, which triggers its sequestration in the cytoplasm and prevents its nuclear translocation. In the nucleus, CRTC2 normally co-activates CREB to drive the expression of key gluconeogenic genes like G6PC and PCK1. Beyond its role in glucose production, CRTC2 also functions as a bridge to the COPII (Coat protein complex II) vesicle transport machinery, specifically interacting with subunits like SEC23A to facilitate the transport of SREBP1 from the endoplasmic reticulum to the Golgi apparatus. This transport is a prerequisite for the proteolytic activation of SREBP1, which then enters the nucleus to induce lipogenic gene expression. By activating AMPK, drugs like metformin can suppress this axis, leading to reduced hepatic glucose output and inhibited de novo lipogenesis, making it a primary therapeutic focus for metabolic diseases.

Other names

AMPK-CRTC2-SEC23 axisAMPK-CRTC2-SREBP1 pathwayAMPK-TORC2-COPII axisHepatic AMPK-CRTC2 signaling axis

AMPK activation leads to the phosphorylation of CRTC2, which inhibits its nuclear activity (reducing gluconeogenesis) and disrupts its interaction with the COPII complex, thereby blocking the ER-to-Golgi transport and subsequent activation of SREBP1 (reducing lipogenesis).