Critical role for PI3-kinase in regulating the use of proteins as an amino acid source

Abstract

Significance Mammalian cells can take up monomeric amino acids through cell-surface transporters or recover amino acids through macropinocytosis and lysosomal catabolism of extracellular proteins. In mammalian cells, nutrient uptake is regulated by growth factors. Yet how growth-factor signaling orchestrates different nutrient uptake routes is unclear. Here, we establish a central role for growth-factor–activated phosphatidylinositol 3-kinase (PI3-kinase) signaling in promoting cellular amino acid uptake and show that distinct effector branches regulate expression of amino acid transporters, and macropinocytosis and lysosomal catabolism of ingested proteins. Therefore, PI3-kinase signaling supports cell proliferation in the presence of various amino acid sources. These findings suggest that oncogenic PI3-kinase pathway activation is a selective advantage for tumor cells proliferating in fluctuating nutrient environments.