Université de Fribourg

The architecture of the Rag GTPase signaling network

Nicastro, Raffaele ; Sardu, Alessandro ; Panchaud, Nicolas ; De Virgilio, Claudio

In: Biomolecules, 2017, vol. 7, no. 3, p. 48

The evolutionarily conserved target of rapamycin complex 1 (TORC1) couples an array of intra- and extracellular stimuli to cell growth, proliferation and metabolism, and its deregulation is associated with various human pathologies such as immunodeficiency, epilepsy, and cancer. Among the diverse stimuli impinging on TORC1, amino acids represent essential input signals, but how they control...

Université de Fribourg

Amino Acids Stimulate TORC1 through Lst4-Lst7, a GTPase-Activating Protein Complex for the Rag Family GTPase Gtr2

Péli-Gulli, Marie-Pierre ; Sardu, Alessandro ; Panchaud, Nicolas ; Raucci, Serena ; Virgilio, Claudio De

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...

Université de Fribourg

Crystal structure of the Ego1-Ego2-Ego3 complex and its role in promoting Rag GTPase-dependent TORC1 signaling

Powis, Katie ; Zhang, Tianlong ; Panchaud, Nicolas ; Wang, Rong ; Virgilio, Claudio De ; Ding, Jianping

In: Cell Research, 2015, vol. 25, no. 9, p. 1043–1059

The target of rapamycin complex 1 (TORC1) integrates various hormonal and nutrient signals to regulate cell growth, proliferation, and differentiation. Amino acid-dependent activation of TORC1 is mediated via the yeast EGO complex (EGOC) consisting of Gtr1, Gtr2, Ego1, and Ego3. Here, we identify the previously uncharacterized Ycr075w-a/Ego2 protein as an additional EGOC component that is...

Université de Fribourg

Amino acid deprivation inhibits TORC1 through a GTPase-activating protein complex for the rag family GTPase Gtr1

Panchaud, Nicolas ; Péli-Gulli, Marie-Pierre ; De Virgilio, Claudio

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...

Université de Fribourg

Identification of a small molecule yeast TORC1 inhibitor with a multiplex screen based on flow cytometry

Chen, Jun ; Young, Susan M. ; Allen, Chris ; Seeber, Andrew ; Péli-Gulli, Marie-Pierre ; Panchaud, Nicolas ; Waller, Anna ; Ursu, Oleg ; Yao, Tuanli ; Golden, Jennifer E. ; Strouse, J. Jacob ; Carter, Mark B. ; Kang, Huining ; Bologa, Cristian G. ; Foutz, Terry D. ; Edwards, Bruce S. ; Peterson, Blake R. ; Aubé, Jeffrey ; Werner-Washburne, Margaret ; Loewith, Robbie J. ; De Virgilio, Claudio ; Sklar, Larry A.

In: ACS Chemical Biology, 2012, vol. 7, no. 4, p. 715–722

TOR (target of rapamycin) is a serine/threonine kinase, evolutionarily conserved from yeast to human, which functions as a fundamental controller of cell growth. The moderate clinical benefit of rapamycin in mTOR-based therapy of many cancers favors the development of new TOR inhibitors. Here we report a high-throughput flow cytometry multiplexed screen using five GFP-tagged yeast clones that...

Université de Fribourg

Mitochondrial genomic dysfunction causes dephosphorylation of SCH9 in the yeast Saccharomyces cerevisiae

Kawai, Shigeyuki ; Urban, Jörg ; Piccolis, Manuele ; Panchaud, Nicolas ; De Virgilio, Claudio ; Loewith, Robbie

In: Eukaryotic Cell, 2011, vol. 10, no. 10, p. 1367-1369

TORC1-dependent phosphorylation of Saccharomyces cerevisiae Sch9 was dramatically reduced upon exposure to a protonophore or in respiration-incompetent ρ⁰ cells but not in respiration-incompetent pet mutants, providing important insight into the molecular mechanisms governing interorganellar signaling in general and retrograde signaling in particular

Université de Fribourg

The Vam6 GEF controls TORC1 by activating the EGO complex

Binda, Matteo ; Péli-Gulli, Marie-Pierre ; Bonfils, Grégory ; Panchaud, Nicolas ; Urban, Jörg ; Sturgill, Thomas W. ; Loewith, Robbie ; De Virgilio, Claudio

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...

Université de Fribourg

The Vam6 GEF controls TORC1 by activating the EGO complex

Binda, Matteo ; Péli-Gulli, Marie-Pierre ; Bonfils, Grégory ; Panchaud, Nicolas ; Urban, Jörg ; Sturgill, Thomas W. ; Loewith, Robbie ; De Virgilio, Claudio

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...