ArticleProceedings of the National Academy of Sciences of the United States of America2022
Structural insights into Ras regulation by SIN1.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 24 citations in OpenAlex.
- COSMIC-Linked Ras Mutations at the Interface Between H-Ras and PI3KγBiochemistry · 2026Article
- COSMIC-Linked Ras Mutations at the Interface Between H-Ras and PI3KγbioRxiv : the preprint server for biology · 2026Article
- Positive cooperativity between RAS-binding and cysteine-rich domains regulates RAF membrane binding kinetics via lateral rebinding.Nature communications · 2026Article
- Time-Resolved Crystallography Reveals the Mechanisms of GTP hydrolysis for N-RAS and the Oncogenic Mutants G12C, G12V and Q61L.bioRxiv : the preprint server for biology · 2025Article
- Making PI3K superfamily enzymes run faster.Advances in biological regulation · 2025Review
- Motif-guided identification of KRAS-interacting proteins.BMC biology · 2024Article
- Targeting the mTOR-Autophagy Axis: Unveiling Therapeutic Potentials in Osteoporosis.Biomolecules · 2024Review
- Targeting mTOR signaling pathways in multiple myeloma: biology and implication for therapy.Cell communication and signaling : CCS · 2024Review
- Negative Regulation of Autophagy during Macrophage Infection byInternational journal of molecular sciences · 2024Article
- Conformational States of the GDP- and GTP-Bound HRAS Affected by A59E and K117R: An Exploration from Gaussian Accelerated Molecular Dynamics.Molecules (Basel, Switzerland) · 2024Article
- The mTORC2 signaling network: targets and cross-talks.The Biochemical journal · 2024Review
- The allosteric mechanism of mTOR activation can inform bitopic inhibitor optimization.Chemical science · 2024Article
- Unmasking the tumourigenic role of SIN1/MAPKAP1 in the mTOR complex 2.Clinical and translational medicine · 2023Review
- An extracellular vesicular mutant KRAS-associated protein complex promotes lung inflammation and tumor growth.Journal of extracellular vesicles · 2023Article
- Dynamic regulation of RAS and RAS signaling.The Biochemical journal · 2023Article
- TOR complex 2 is a master regulator of plasma membrane homeostasis.The Biochemical journal · 2022Article
- New mechanistic insights into the RAS-SIN1 interaction at the membrane.Frontiers in cell and developmental biology · 2022Article
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Over the years it has been established that SIN1, a key component of mTORC2, could interact with Ras family small GTPases through its Ras-binding domain (RBD). The physical association of Ras and SIN1/mTORC2 could potentially affect both mTORC2 and Ras-ERK pathways. To decipher the precise molecular mechanism of this interaction, we determined the high-resolution structures of HRas/KRas-SIN1 RBD complexes, showing the detailed interaction interface. Mutation of critical interface residues abolished Ras-SIN1 interaction and in SIN1 knockout cells we demonstrated that Ras-SIN1 association promotes SGK1 activity but inhibits insulin-induced ERK activation. With structural comparison and competition fluorescence resonance energy transfer (FRET) assays we showed that HRas-SIN1 RBD association is much weaker than HRas-Raf1 RBD but is slightly stronger than HRas-PI3K RBD interaction, providing a possible explanation for the different outcome of insulin or EGF stimulation. We also found that SIN1 isoform lacking the PH domain binds stronger to Ras than other longer isoforms and the PH domain appears to have an inhibitory effect on Ras-SIN1 binding. In addition, we uncovered a Ras dimerization interface that could be critical for Ras oligomerization. Our results advance our understanding of Ras-SIN1 association and crosstalk between growth factor-stimulated pathways.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.