Phosphatidylinositol-3 kinase (PI3K)–Protein kinase B (Akt)–Akt substrate of 160 kDa (AS160) signaling pathway (PI3K-Akt-AS160 pathway)

The Phosphatidylinositol-3 kinase (PI3K)–Protein kinase B (Akt)–Akt substrate of 160 kDa (AS160) signaling pathway is a central regulatory cascade that mediates insulin-dependent glucose uptake in peripheral tissues such as skeletal muscle and adipose tissue (Sakamoto & Holman, 2008, PMID: 18448544). Upon insulin stimulation, the activation of PI3K leads to the production of phosphatidylinositol-3,4,5-trisphosphate (PIP3), which recruits the serine/threonine kinase Akt to the plasma membrane for activation (Manning & Toker, 2017, PMID: 28235194). Activated Akt subsequently phosphorylates AS160 (also known as TBC1D4) at multiple sites, most notably Thr642. AS160 normally functions as a GTPase-activating protein (GAP) that maintains Rab proteins in an inactive, GDP-bound state, thereby sequestering glucose transporter 4 (GLUT4) within intracellular vesicles (Sano et al., 2003, PMID: 12529335). Phosphorylation by Akt inhibits AS160's GAP activity, allowing Rab proteins (such as Rab10) to load with GTP and facilitate the translocation and fusion of GLUT4 vesicles with the plasma membrane. Impairment of this pathway is a primary driver of insulin resistance and is strongly associated with the pathogenesis of Type 2 diabetes mellitus (Cartee, 2015, PMID: 25851614). Conversely, hyperactivation of the upstream PI3K/Akt components is a frequent occurrence in various cancers, making this pathway a major focus for both metabolic and oncological drug development.

Other names

PI3K/Akt/AS160 axisInsulin-stimulated GLUT4 translocation pathwayTBC1D4 signaling cascadePI3K-Akt-TBC1D4 pathway

Activation of PI3K generates PIP3, which recruits and activates Akt; Akt then phosphorylates and inactivates AS160 (a Rab-GAP), leading to Rab-mediated translocation of GLUT4 to the plasma membrane for glucose uptake.