In: Science Advances, 2019, vol. 5, no. 9, p. eaax8164
The Rag/Gtr GTPases serve as a central module in the nutrient-sensing signaling network upstream of TORC1. In yeast, the anchoring of Gtr1-Gtr2 to membranes depends on the Ego1-Ego2-Ego3 ternary complex (EGO-TC), resulting in an EGO- TC-Gtr1-Gtr2 complex (EGOC). EGO-TC and human Ragulator share no obvious sequence similarities and also differ in their composition with respect to the number of ...
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In: Molecular Cell, 2019, vol. 73, no. 2, p. 325-338.e8
The eukaryotic TORC1 kinase is a homeostatic controller of growth that integrates nutritional cues and mediates signals primarily from the surface of lysosomes or vacuoles. Amino acids activate TORC1 via the Rag GTPases that combine into structurally conserved multi-protein complexes such as the EGO complex (EGOC) in yeast. Here we show that Ego1, which mediates membrane-anchoring of EGOC via...
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In: Cell Discovery, 2017, vol. 3, p. 17012
Eukaryotic cell cycle progression through G1–S is driven by hormonal and growth- related signals that are transmitted by the target of rapamycin complex 1 (TORC1) pathway. In yeast, inactivation of TORC1 restricts G1–S transition due to the rapid clearance of G1 cyclins (Cln) and the stabilization of the B-type cyclin (Clb) cyclin- dependent kinase (CDK) inhibitor Sic1. The latter mechanism...
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In: Cell Reports, 2017, vol. 20, no. 2, p. 281–288
Amino acids stimulate the eukaryotic target of rapamycin complex 1 (TORC1), and hence growth, through the Rag GTPases and their regulators. Among these, the yeast Lst4-Lst7 Rag GTPase GAP complex clusters, as we previously reported, at the vacuolar membrane upon amino acid starvation. In response to amino acid refeeding, it activates the Rag GTPase-TORC1 branch and is then dispersed from the...
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In: Cell Reports, 2015, vol. 13, no. 1, p. 1–7
Rag GTPases assemble into heterodimeric complexes consisting of RagA or RagB and RagC or RagD in higher eukaryotes, or Gtr1 and Gtr2 in yeast, to relay amino acid signals toward the growth-regulating target of rapamycin complex 1 (TORC1). The TORC1-stimulating state of Rag GTPase heterodimers, containing GTP- and GDP-loaded RagA/B/Gtr1 and RagC/D/Gtr2, respectively, is maintained in part by the...
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In: Journal of Cell Science, 2015, vol. 128, no. 13, p. 2278–2292
Membrane fusion at the vacuole depends on a conserved machinery that includes SNAREs, the Rab7 homolog Ypt7 and its effector HOPS. Here, we demonstrate that Ypt7 has an unexpected additional function by controlling membrane homeostasis and nutrient-dependent signaling on the vacuole surface. We show that Ivy1, the yeast homolog of mammalian missing-in-metastasis (MIM), is a vacuolar effector of...
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In: PLoS ONE, 2014, vol. 9, no. 8, p. e104194
The evolutionarily conserved target of rapamycin complex 1 (TORC1) controls growth-related processes such as protein, nucleotide, and lipid metabolism in response to growth hormones, energy/ATP levels, and amino acids. Its deregulation is associated with cancer, type 2 diabetes, and obesity. Among other substrates, mammalian TORC1 directly phosphorylates and inhibits the phosphatidate phosphatase...
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In: Science Signaling, 2013, vol. 6, no. 277, p. ra42
The Rag family of guanosine triphosphatases (GTPases) regulates eukaryotic cell growth in response to amino acids by activating the target of rapamycin complex 1 (TORC1). In humans, this pathway is often deregulated in cancer. In yeast, amino acids promote binding of GTP (guanosine 5'-triphosphate) to the Rag family GTPase Gtr1, which, in combination with a GDP (guanosine diphosphate)–bound...
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In: Structure, 2012, vol. 20, no. 12, p. 2151–2160
The yeast EGO complex, consisting of Gtr1, Gtr2, Ego1, and Ego3, localizes to the endosomal and vacuolar membranes and plays a pivotal role in cell growth and autophagy regulation through relaying amino acid signals to activate TORC1. Here, we report the crystal structures of a wild-type and a mutant form of Saccharomyces cerevisiae Ego3. Ego3 assumes a homodimeric structure similar to that of...
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In: Molecular Cell, 2009, vol. 35, no. 5, p. 563-573
The target of rapamycin complex 1 (TORC1) is a central regulator of eukaryotic cell growth that is activated by a variety of hormones (e.g., insulin) and nutrients (e.g., amino acids) and is deregulated in various cancers. Here, we report that the yeast Rag GTPase homolog Gtr1, a component of the vacuolar-membrane-associated EGO complex (EGOC), interacts with and activates TORC1 in an...
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