Substrate Selectivity As a Paradigm Shift in Mtorc1 Signaling.

mTORC1 is a central regulator of cell growth and metabolism, classically viewed as a binary switch that promotes anabolic programs while suppressing catabolic pathways. Recent work advances this simplified model by revealing that mTORC1 signaling is highly substrate-specific, with distinct classes of substrates differentially regulated according to their modes of recruitment and subcellular localization. In this review, we discuss emerging evidence demonstrating that mTORC1 activity and its lysosomal localization can be functionally uncoupled, enabling selective phosphorylation of lysosomal versus non-lysosomal targets. We highlight how upstream regulatory pathways and post-translational modifications shape these substrate-specific outputs, and consider the implications of downstream uncoupling for the fundamental understanding of mTORC1 biology as well as human health and disease.