Amino acid starvation response pathway (AAR pathway)

The amino acid starvation response pathway (AAR pathway) is a conserved cellular signaling cascade activated when essential amino acids are limited. Sensing of uncharged tRNAs by the kinase GCN2 leads to phosphorylation of the translation factor eIF2α, resulting in a global decrease in protein synthesis and selective translation of the transcription factor ATF4. ATF4 then regulates genes involved in amino acid metabolism, transport, autophagy, and stress adaptation. This pathway is essential for maintaining cellular homeostasis during nutrient deprivation, is involved in metabolic and immune adaptation, and has become a focus in cancer therapy by exploiting the high amino acid demand of tumor cells. However, it is a multifactorial pathway rather than a single molecular target, and thus not suitable as a therapeutic target in the conventional sense.

Other names

Amino acid response pathwayAAR pathwayamino acid deprivation responseGCN2/ATF4 pathway

Activation or inhibition of pathway components (GCN2 activators mimic amino acid starvation, increasing ATF4 and triggering downstream stress responses or autophagy) Amino acid depletion therapies induce apoptosis or sensitize cancer cells to DNA-damaging or immunotherapies