A tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1

By L. Bar-Peled, Lynne Chantranupong, A. Cherniack, Walter W. Chen, K. Ottina, Brian C. Grabiner, Eric D. Spear, Scott L. Carter, Matthew Meyerson, David M. Sabatini. Science, 2013

1,053 citations recorded by the source corpus.

Limiting mTORC1 The mTORC1 protein kinase complex has important functions linking metabolism to cell growth and its functions are disrupted in common diseases, including cancer and diabetes. Bar-Peled et al. (p. 1100; see the Perspective by Shaw) discovered regulatory components that help turn down signaling by mTORC1 when cells are deprived of amino acids. Two complexes of proteins, GATOR1 and GATOR2, have opposite effects on activity and cellular localization of mTORC1. Components of the GATOR1 complex negatively regulate mTORC1 and appear to function as tumor supressors. Cancers with loss of GATOR1 function may be particularly amenable to therapeutic strategies that limit activity of mTORC1. A protein complex identified as a negative regulator of the mTORC1 protein kinase complex has tumor suppressor functions. [Also see Perspective by Shaw] The mTOR complex 1 (mTORC1) pathway promotes cell growth in response to many cues, including amino acids, which act through the Rag guanosine triphosphatases (GTPases) to promote mTORC1 translocation to the lysosomal surface, its site of activation. Although progress has been made in identifying positive regulators of the Rags, it is unknown if negative factors also exist. Here, we identify GATOR as a complex that interacts with the Rags and is composed of two subcomplexes we call GATOR1 and -2. Inhibition of GATOR1 subunits (DEPDC5, Nprl2, and Nprl3) makes mTORC1 signaling resistant to amino acid deprivation. In contrast, inhibition of GATOR2 subunits (Mios, WDR24, WDR59, Seh1L, and Sec13) suppresses mTORC1 signaling, and epistasis analysis shows that GATOR2 negatively regulates DEPDC5. GATOR1 has GTPase-activating protein (GAP) activity for RagA and RagB, and its components are mutated in human cancer. In cancer cells with inactivating mutations in GATOR1, mTORC1 is hyperactive and insensitive to amino acid starvation, and such cells are hypersensitive to rapamycin, an mTORC1 inhibitor. Thus, we identify a key negative regulator of the Rag GTPases and reveal that, like other mTORC1 regulators, Rag function can be deregulated in cancer.

Subfields: Cell Biology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/be923e86e999162c24087da3c9a0cd48c073847c

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Citations in the corpus

mTOR Signaling in Growth, Metabolism, and Disease (2017, background): “Several components of the nutrient sensing input to mTORC1 have also been implicated in cancer progression, including all three subunits of the GATOR1 complex, which are mutated with low frequency in glioblastoma (Bar-Peled et al., 2013), as well as RagC, which was recently found to be mutated at hi”
Nutrient sensing and TOR signaling in yeast and mammals (2017, neutral): “GATOR1 is composed of DEPDC5 (DEP domain-containing protein 5), NPRL2 (nitrogen permease regulator 2-like protein), and NPRL3 where DEPDC5 is thought to possess the GAP activity toward RAGA/B (Bar-Peled et al , 2013; Panchaud et al , 2013a).”
mTOR Signaling in Growth, Metabolism, and Disease. (2017, background): “Several components of the nutrient sensing input to mTORC1 have also been implicated in cancer progression, including all three subunits of the GATOR1 complex, which are mutated with low frequency in glioblastoma (Bar-Peled et al., 2013), as well as RagC, which was recently found to be mutated at hi”
The CASTOR proteins are arginine sensors for the mTORC1 pathway (2016, neutral): “The GATOR2 complex, which has five subunits (mios, WDR24, WDR59, sec13, seh1L), acts upstream or parallel to GATOR1 and is a key positive regulator of the mTORC1 pathway, although its molecular function is unknown (Bar-Peled et al., 2013).”
Nutrient sensing and signaling in the yeast Saccharomyces cerevisiae (2014, background): “The GAP activity of SEACIT is also conserved, as the orthologous complex in Drosophila and human cells, known as GATOR1, also acts as a GAP toward RagA and RagB (Bar-Peled et al., 2013).”
Regulation of mTORC1 by amino acids (2014, neutral): “Early experiments with Ragulator hinted at the auxiliary roles of this complex: Ragulator preferentially bound to Rags in their inactive state, an interaction that was driven by the nucleotide state of RagA/B (48).”
Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease (2023, background): “53 Sestrin2 was discovered as a GATOR2 interacting protein partner that senses cytosolic amino acid.”
The Neurology of mTOR (2014, neutral): “Human mutations in DEPDC5, a component of the GATOR complex, have been linked to both epilepsy with cerebral malformations and nonlesional epilepsy (Bar-Peled et al., 2013; Dibbens et al., 2013; Scheffer et al., 2014).”
Sestrin2 is a leucine sensor for the mTORC1 pathway (2015, background): “Ragulator anchors the Rag heterodimers to the lysosome and has nucleotide exchange activity for RagA and RagB (21, 25).”