Abstract
Solute Carriers (SLCs) are involved in the transport of substances across lipid bilayers, including nutrients like amino acids. Amino acids increase the activity of the microenvironmental sensor mechanistic Target of Rapamycin Complex 1 (mTORC1) to promote cellular growth and anabolic processes. They can be brought in to cells by a wide range of SLCs including the closely related Proton-assisted Amino acid Transporter (PAT or SLC36) and Sodium-coupled Neutral Amino acid Transporter (SNAT or SLC38) families. More than a decade ago, the first evidence emerged that members of the PAT family can act as amino acid-stimulated receptors, or so-called “transceptors,” connecting amino acids to mTORC1 activation. Since then, further studies in human cell models have suggested that other PAT and SNAT family members, which share significant homology within their transmembrane domains, can act as transceptors. A paradigm shift has also led to the PATs and SNATs at the surface of multiple intracellular compartments being linked to the recruitment and activation of different pools of mTORC1. Much focus has been on late endosomes and lysosomes as mTORC1 regulatory hubs, but more recently a Golgi-localized PAT was shown to be required for mTORC1 activation. PATs and SNATs can also traffic between the cell surface and intracellular compartments, with regulation of this movement providing a means of controlling their mTORC1 regulatory activity. These emerging features of PAT and SNAT amino acid sensors, including the transceptor mechanism, have implications for the pharmacological inhibition of mTORC1 and new therapeutic interventions.
Highlights
Specialty section: This article was submitted to Experimental Pharmacology and Drug Discovery, a section of the journal Frontiers in Pharmacology
A paradigm shift has led to the PATs and SNATs at the surface of multiple intracellular compartments being linked to the recruitment and activation of different pools of mechanistic Target of Rapamycin Complex 1 (mTORC1)
We review the evidence that members of the PAT (SLC36) and SNAT (SLC38) amino acid transporter families act as PAT/SNAT Amino Acid Sensors transceptors to control mTORC1 signaling and that this takes place on intracellular membranes
Summary
Many nutrients are shuttled across the plasma membrane into the cytosol by transporters. Elegant experiments involving the transport of the non-metabolisable SNAT2 substrate MeAIB (αmethylaminoisobutyrate) demonstrated that this compound could activate mTORC1 signaling via SNAT2 during amino acid starvation Under these specific conditions, MeAIB increased cell proliferation in MCF7 breast cancer and L6 myotubes (Pinilla et al, 2011). Reports identifying the human PATs as mTORC1 regulators emerged shortly after their established sites of action, the LELs, were shown to be key places where mTORC1 signaling is controlled by amino acids via the Rag GTPases, central components of an amino acid sensing complex required for mTORC1 recruitment and activation on these compartments (Sancak et al, 2008). It will be important to check that this Golgi-located SNAT2 is not involved in mTORC1 regulation in future studies
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