EPHA2 regulates the abundance of amino acid transporter LAT3 through its receptor tyrosine kinase activity
A photo-lysine optoproteomics screen mapped 167 membrane-associated LAT3 interactors in living cells. EPHA2 was the only receptor kinase found and negatively regulates LAT3 stability via phosphorylation at tyrosine 251.
LAT3 (SLC43A1) is a sodium-independent transporter for neutral and branched-chain amino acids, and its activity has been linked to both normal development and cancer. Despite its importance, how LAT3 is regulated at the protein level has remained poorly defined. A new study set out to map the membrane-associated protein interactions of LAT3 in living cells, aiming to identify regulators that control its abundance and function.
The authors used a photo-lysine–based optoproteomics strategy combined with affinity purification–mass spectrometry. This approach allowed them to capture transient and membrane-proximal interactions of LAT3 under native conditions. From this screen, they identified 167 high-confidence membrane-associated interactors. After excluding LAT3 itself, 43 of these candidates localized to the plasma membrane. Among them, EPHA2 was the only receptor tyrosine kinase detected.
Biochemical assays confirmed that EPHA2 directly interacts with LAT3 and phosphorylates it at tyrosine 251. When EPHA2 activity was inhibited, LAT3 protein abundance increased. This suggests that EPHA2 kinase activity negatively regulates LAT3 stability through a post-translational degradation pathway. The findings provide a mechanistic link between a receptor tyrosine kinase and the turnover of an amino acid transporter.
The study offers a comprehensive membrane interactome for LAT3, but several caveats apply. The work is cell-based and does not establish in vivo consequences or tissue-specific effects. The degradation pathway and the precise E3 ligase involved remain to be defined. Moreover, the functional impact of LAT3 phosphorylation on transport kinetics was not fully explored. As a research-use-only briefing, this does not constitute medical or clinical guidance, and no therapeutic claims are made. The dataset provides a foundation for further studies on how EPHA2 and other membrane proteins regulate amino acid transport in physiology and disease.