Npr2, Yeast Homolog of the Human Tumor Suppressor
            <i>NPRL2</i>
            , Is a Target of Grr1 Required for Adaptation to Growth on Diverse Nitrogen Sources

Spielewoy, Nathalie; Guaderrama, Marisela; Wohlschlegel, James A.; Ashe, Mabelle; Wittenberg, Curt

doi:10.1128/ec.00192-09

Cited by 23 publications

(38 citation statements)

References 33 publications

(59 reference statements)

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“…As NPRL2, yeast Npr2 belongs to a recently identified GTPase activating complex, transmitting an amino-acid deprivation signal to TORC1 (refs 45,46). Npr2-lacking cells are reported to be affected for growth on ammonium but the underlying mechanism is unknown 7,44 . Cells expressing Mep2 as sole Mep-Amt protein and lacking Npr2 displayed strongly altered growth in the presence of low ammonium (Fig.…”

Section: Resultsmentioning

confidence: 99%

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The TORC1 effector kinase Npr1 fine tunes the inherent activity of the Mep2 ammonium transport protein

et al. 2014

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The TORC1 complex controls cell growth upon integrating nutritional signals including amino-acid availability. TORC1 notably adapts the plasma membrane protein content by regulating arrestin-mediated endocytosis of amino-acid transporters. Here we demonstrate that TORC1 further fine tunes the inherent activity of the ammonium transport protein, Mep2, a yeast homologue of mammalian Rhesus factors, independently of arrestin-mediated endocytosis. The TORC1 effector kinase Npr1 and the upstream TORC1 regulator Npr2 control Mep2 transport activity by phospho-silencing a carboxy-terminal autoinhibitory domain. Under poor nitrogen supply, Npr1 enables Mep2 S457 phosphorylation and thus ammonium transport activity. Supplementation of the preferred nitrogen source glutamine leads to Mep2 inactivation and instant S457 dephosphorylation via plasma membrane Psr1 and Psr2 redundant phosphatases. This study underscores that TORC1 also adjusts nutrient permeability to regulate cell growth in a fast and flexible response to environmental perturbation, establishing a hierarchy in the transporters to be degraded, inactivated or maintained active at the plasma membrane.

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Section: Resultsmentioning

confidence: 99%

“…Yeast Npr2 belongs to a family of conserved proteins of unknown function; its human orthologue, NPRL2, being recognized as a tumour suppressor 43,44 . As NPRL2, yeast Npr2 belongs to a recently identified GTPase activating complex, transmitting an amino-acid deprivation signal to TORC1 (refs 45,46).…”

Section: Resultsmentioning

confidence: 99%

The TORC1 effector kinase Npr1 fine tunes the inherent activity of the Mep2 ammonium transport protein

et al. 2014

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“…Although E3 activity for HOPS/CORVET has not yet been demonstrated, the RING domains of Vps8 and Vps18 are required for VPS-C function (19). Interestingly, Npr2 interacts with Grr1, the F-box component of SCF Grr1 E3 ubiquitin ligase (62). This particular ligase often interacts with PEST motif carrying proteins in phosphorylation dependent manner.…”

Section: The Sea Complex Belongs To a Superfamily Of Coatingmentioning

confidence: 99%

A Conserved Coatomer-related Complex Containing Sec13 and Seh1 Dynamically Associates With the Vacuole in Saccharomyces cerevisiae

Dokudovskaya

Waharte

Schlessinger

et al. 2011

Molecular & Cellular Proteomics

122

156

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The presence of multiple membrane-bound intracellular compartments is a major feature of eukaryotic cells. Many of the proteins required for formation and maintenance of these compartments share an evolutionary history. Here, we identify the SEA (Seh1-associated) protein complex in yeast that contains the nucleoporin Seh1 and Sec13, the latter subunit of both the nuclear pore complex and the COPII coating complex. The SEA complex also contains Npr2 and Npr3 proteins (upstream regulators of TORC1 kinase) and four previously uncharacterized proteins (Sea1-Sea4). Combined computational and biochemical approaches indicate that the SEA complex proteins possess structural characteristics similar to the membrane coating complexes COPI, COPII, the nuclear pore complex, and, in particular, the related Vps class C vesicle tethering complexes HOPS and CORVET. The SEA complex dynamically associates with the vacuole in vivo. Genetic assays indicate a role for the SEA complex in intracellular trafficking, amino acid biogenesis, and response to nitrogen starvation. These data demonstrate that the SEA complex is an additional member of a family of membrane coating and vesicle tethering assemblies, extending the repertoire of protocoatomer-related complexes. Molecular & Cellular

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“…The Iml1 complex, which has been renamed the "GTPase-activating proteins toward Rags 1" (GATOR1) complex in higher eukaryotes, functions as a GTPase-activating protein complex that inactivates RagsA/B or Gtr1 in mammals and yeast, respectively, thus preventing the activation of TORC1 (3,4). In the yeast Saccharomyces cerevisiae, mutations in the Iml1 complex components Npr2 and Npr3 result in a failure to down-regulate TORC1 activity in response to amino acid starvation and block meiosis and sporulation (6)(7)(8)(9). As is observed in yeast, in Drosophila, Nprl2 and Nprl3 mediate a critical response to amino acid starvation (10).…”

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confidence: 99%

TORC1 regulators Iml1/GATOR1 and GATOR2 control meiotic entry and oocyte development in Drosophila

Wei

Reveal

Reich

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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In single-cell eukaryotes the pathways that monitor nutrient availability are central to initiating the meiotic program and gametogenesis. In Saccharomyces cerevisiae an essential step in the transition to the meiotic cycle is the down-regulation of the nutrient-sensitive target of rapamycin complex 1 (TORC1) by the increased minichromosome loss 1/ GTPase-activating proteins toward Rags 1 (Iml1/ GATOR1) complex in response to amino acid starvation. How metabolic inputs influence early meiotic progression and gametogenesis remains poorly understood in metazoans. Here we define opposing functions for the TORC1 regulatory complexes Iml1/ GATOR1 and GATOR2 during Drosophila oogenesis. We demonstrate that, as is observed in yeast, the Iml1/GATOR1 complex inhibits TORC1 activity to slow cellular metabolism and drive the mitotic/meiotic transition in developing ovarian cysts. In iml1 germline depletions, ovarian cysts undergo an extra mitotic division before meiotic entry. The TORC1 inhibitor rapamycin can suppress this extra mitotic division. Thus, high TORC1 activity delays the mitotic/ meiotic transition. Conversely, mutations in Tor, which encodes the catalytic subunit of the TORC1 complex, result in premature meiotic entry. Later in oogenesis, the GATOR2 components Mio and Seh1 are required to oppose Iml1/GATOR1 activity to prevent the constitutive inhibition of TORC1 and a block to oocyte growth and development. To our knowledge, these studies represent the first examination of the regulatory relationship between the Iml1/GATOR1 and GATOR2 complexes within the context of a multicellular organism. Our data imply that the central role of the Iml1/GATOR1 complex in the regulation of TORC1 activity in the early meiotic cycle has been conserved from single cell to multicellular organisms.

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Npr2, Yeast Homolog of the Human Tumor Suppressor NPRL2 , Is a Target of Grr1 Required for Adaptation to Growth on Diverse Nitrogen Sources

Cited by 23 publications

References 33 publications

The TORC1 effector kinase Npr1 fine tunes the inherent activity of the Mep2 ammonium transport protein

The TORC1 effector kinase Npr1 fine tunes the inherent activity of the Mep2 ammonium transport protein

A Conserved Coatomer-related Complex Containing Sec13 and Seh1 Dynamically Associates With the Vacuole in Saccharomyces cerevisiae

TORC1 regulators Iml1/GATOR1 and GATOR2 control meiotic entry and oocyte development in Drosophila

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