Cells have their own growth switches. When enough nutrients, especially amino acids, are available, cells turn on this switch and begin to grow. Researchers from KAIST and Yonsei University have elucidated the molecular mechanism by which amino acid signals activate this cell growth switch. This discovery is expected to open new avenues for anticancer therapy that targets abnormal proliferation signaling in tumor cells.
KAIST (Chairman Bae Choong-sik) announced on July 26 that a research team led by Professor Park Hee-sung and Professor Kang Jin-young from the Department of Chemistry, in collaboration with Professor Kim Sung-hoon’s team from Yonsei University, has identified a molecular mechanism linking amino acid stimulation and mTORC1-dependent proliferation signaling.
Cells continually monitor whether there are enough amino acids, the basic building blocks of proteins, in their surroundings and adjust cell growth, protein synthesis, and energy use accordingly. Central to this process is mTORC1 (mammalian target of rapamycin complex 1), a protein complex that acts as a growth switch for cells.
mTORC1 promotes cell growth, protein synthesis, and metabolism when nutrients and energy are abundant. However, overactivation of mTORC1 can cause cells to grow and proliferate more than necessary, a pattern of dysregulation observed in many cancers. For this reason, mTORC1 has long been considered a key target for anticancer drug development. However, exactly how cells detect external nutritional signals and translate them into mTORC1 activation is still not fully understood.
The research team focused on multi-tRNA synthetase complexes (MSCs), large protein assemblies composed of multiple aminoacyl-tRNA synthetases and scaffold proteins. Aminoacyl-tRNA synthetases are best known for their critical role in protein synthesis, linking specific amino acids to their cognate tRNAs, but the research team showed that MSCs release LARS1 in response to amino acid stimulation, thereby linking nutrient availability to growth signaling.
The central player within MSCs was found to be a protein called LARS1 (leucyl-tRNA synthetase 1), an enzyme that binds leucine to its corresponding tRNA and also functions as an intracellular leucine sensor. When cells receive a signal that nutrients are sufficient, LARS1 undergoes phosphorylation. This is a modification in which a small chemical tag is added to a protein, changing its function or binding behavior.
This relationship can be expressed as: MSCs are control centers where multiple proteins wait, and LARS1 is a field agent dispatched to flip the growth switch. When nutrients are enriched, LARS1 receives a phosphorylation “unfolding signal” and dissociates from IARS1, the protein that anchors LARS1 to MSCs, thereby releasing it from the complex. The released LARS1 then activates mTORC1.
In other words, when nutrients are scarce, LARS1 remains bound within mesenchymal stem cells and growth signals remain off. When nutrients are sufficient, LARS1 is released from MSCs and turns on mTORC1.
To investigate the structural basis of this process, the research team used cryogenic electron microscopy (cryo-EM). This is a technique that visualizes protein complexes in three dimensions with near-atomic resolution by rapidly freezing samples at extremely low temperatures. This allowed the researchers to determine how LARS1 and IARS1 bind to each other and structurally explain how phosphorylation disrupts the interaction.
The results showed that although LARS1 and IARS1 are normally strongly bound, amino acid stimulation induces phosphorylation of LARS1 and weakens its interaction with IARS1. This allows LARS1 to dissociate from MSCs and activate mTORC1.
The researchers also engineered phosphomimetic LARS1 mutants (mutant proteins designed to mimic phosphorylation states) and found that these mutants significantly enhanced mTORC1 activity. This confirmed that phosphorylation of LARS1 functions as an important molecular switch that converts nutritional signals into cell proliferation signals.
The importance of this study lies in mapping the specific molecular details of how cells sense amino acids and use that information to activate growth switches. In particular, the study revealed that when MSCs, a complex involved in protein synthesis, receive nutritional signals, they release the constituent protein LARS1, which activates cell proliferation signaling.
Some existing anticancer drugs work by directly inhibiting the cell growth switch mTORC1. However, mTORC1 is also required for normal cell growth and metabolism, so its direct inhibition may also affect normal cells.
The researchers hope that further identification of the kinases involved in LARS1 phosphorylation and their regulatory mechanisms may lead to more precise anti-cancer strategies that do not block mTORC1 itself, but instead block proliferative signals further upstream before they reach mTORC1.
The study, co-first authored by Youjin Kim and Joo-Chan Kim from the KAIST Department of Chemistry, was published online. nature communications June 11th.
sauce:
Korea Advanced Institute of Science and Technology (KAIST)
Reference magazines:
Kim, Y. others. (2026). Cryo-EM structure of the LARS1:IARS1 complex reveals a nutrient-responsive switch that controls mTORC1 signaling. nature communications. DOI: 10.1038/s41467-026-74085-x. https://www.nature.com/articles/s41467-026-74085-x
