Mechanistic target of rapamycin complex 1 (mTORC1)-Eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) signaling axis (mTORC1-4E-BP1)

The Mechanistic target of rapamycin complex 1-Eukaryotic translation initiation factor 4E-binding protein 1 (mTORC1-4E-BP1) signaling axis is a fundamental regulatory pathway that couples nutrient and energy availability to the control of protein synthesis and cell growth [1, 5]. mTORC1, a multi-protein kinase complex, serves as the master regulator by phosphorylating 4E-BP1 at multiple sites, which induces its dissociation from the cap-binding protein eIF4E [2, 7]. Once released, eIF4E facilitates the assembly of the eIF4F initiation complex on the 5' cap of mRNAs, promoting the translation of proteins required for cell cycle progression and survival [1, 5]. Dysregulation of this axis is frequently observed in various malignancies and fibrotic diseases, where it drives pathological cell proliferation and extracellular matrix production [3, 11]. While first-generation mTOR inhibitors like rapamycin only partially suppress 4E-BP1 phosphorylation, second-generation ATP-competitive inhibitors and third-generation bivalent inhibitors (e.g., RapaLink-1) provide more comprehensive blockade of this signaling node [8, 13]. Consequently, the phosphorylation status of 4E-BP1 is widely utilized as a critical biomarker for assessing the efficacy of mTOR-targeted therapies in clinical and preclinical settings [7, 10].

Other names

mTORC1/4E-BP1 axismTORC1/4E-BP1 pathwaymTORC1-4EBP1 signalingmTORC1-4EBP1 signaling axis

Inhibition of the kinase activity of the Mechanistic target of rapamycin complex 1 (mTORC1), which prevents the phosphorylation of Eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) [1, 2]. This maintains 4E-BP1 in its unphosphorylated, active state, where it binds to and sequesters Eukaryotic translation initiation factor 4E (eIF4E), thereby blocking the assembly of the eIF4F complex and inhibiting cap-dependent mRNA translation [1, 5].