SH3BP4 Is a Negative Regulator of Amino Acid-Rag GTPase-mTORC1 Signaling
Open accessAbstract
Amino acids stimulate cell growth and suppress autophagy through activation of mTORC1. The activation of mTORC1 by amino acids is mediated by Rag guanosine triphosphatase (GTPase) heterodimers on the lysosome. The molecular mechanism by which amino acids regulate the Rag GTPase heterodimers remains to be elucidated. Here, we identify SH3 domain-binding protein 4 (SH3BP4) as a binding protein and a negative regulator of Rag GTPase complex. SH3BP4 binds to the inactive Rag GTPase complex through its Src homology 3 (SH3) domain under conditions of amino acid starvation and inhibits the formation of active Rag GTPase complex. As a consequence, the binding abrogates the interaction of mTORC1 with Rag GTPase complex and the recruitment of mTORC1 to the lysosome, thus inhibiting amino acid-induced mTORC1 activation and cell growth and promoting autophagy. These results demonstrate that SH3BP4 is a negative regulator of the Rag GTPase complex and amino acid-dependent mTORC1 signaling.
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Infection-induced autophagy by IFN-γ activation or by starvation requires activation of the small GTPase LRG47 (IRGM in humans).
“Infection-induced autophagy by IFN-γ activation or by starvation requires activation of the small GTPase LRG47 (IRGM in humans) (76, 77).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [77]
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- Sancak Y Bar-Peled L Zoncu R Markhard AL Nada S Sabatini DM Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids Cell 141 290 303 20381137 PMC3024592
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- Authors
- Kim, Y.-M., Stone, M., Hwang, T. H., Kim, Y.-G., Dunlevy, J. R., Griffin, T. J., & Kim, D.-H.
- Affiliations
- University of Minnesota (US)
- Pohang University of Science and Technology (KR)
- University of North Dakota (US)
- Corresponding author
- Kim, Do-Hyung
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2012-06
- Volume
- 46
- Issue
- 6
- Pages
- 833-846
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC3389276
- OpenAlex
- W2158562618
- Cited by
- 88
- References
- 39
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 2 · 2023: 3 · 2022: 8 · 2021: 8 · 2020: 4 · 2019: 5 · 2018: 10 · 2017: 8 · 2016: 7 · 2015: 8 · 2014: 8 · 2013: 7 · 2012: 2
- FWCI
- 3.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Minnesota
- National Institute of General Medical Sciences (GM097057, R01GM097057)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK072004, P30DK050456, R56DK072004, DK083474, R56DK083474, DK050456)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- Rag GTPases, mTORC1 signaling, amino acid signaling, autophagy, lysosomes, amino acid starvation, cell growth, SH3 domain, negative regulation
- MeSH terms
- Amino Acids, Animals, Autophagy, Binding Sites, Cell Line, Guanosine, Humans, Lysosomes, Signal Transduction, src Homology Domains, Adaptor Proteins, Signal Transducing, Mice, HEK293 Cells, TOR Serine-Threonine Kinases
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