Roles for PI(3,5)P<sub>2</sub> in nutrient sensing through TORC1

Jin, Natsuko; Mao, Kai; Jin, Yui; Tevzadze, Gela G.; Kauffman, Emily J.; Park, Su‐Jin; Bridges, Dave; Loewith, Robbie; Saltiel, Alan R.; Klionsky, Daniel J.; Weisman, Lois S.

doi:10.1091/mbc.e14-01-0021

Cited by 78 publications

(155 citation statements)

References 85 publications

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“…In response to ROS (reactive oxygen species), the TSC complex localizes to peroxisomes by binding to PEX19 (peroxisomal biogenesis factor 19) and PEX5 where it inactivates Rheb and mTORC1 to drive autophagy (122; 123). Phospho-lipids also control mTORC1 subcellular localization, reinforcing the emerging concept of endomembranes as important sites for mTORC1 activation (124; 125). The class III lipid kinase Vps34 and the class II lipid kinase PI3K-C2alpha, which generate the phospholipid PI(3)P on endomembranes, functions in an mTORC1 amino acid sensing pathway (91; 92; 124).…”

Section: The Lysosome As a Critical Platform For Upstream Signal Intementioning

confidence: 73%

“…Emerging data on the importance of phospholipids and vesicular trafficking in mTORC1 regulation (91; 92; 124; 125) support the idea that specific membrane sub-compartments may control mTORC1 (and mTORC2) differentially in response to different types of upstream signals and may translate these cues into different types of cellular responses. At this point, we understand mTORC2 subcellular localization poorly.…”

Section: Future Directionsmentioning

confidence: 94%

“…The class III lipid kinase Vps34 and the class II lipid kinase PI3K-C2alpha, which generate the phospholipid PI(3)P on endomembranes, functions in an mTORC1 amino acid sensing pathway (91; 92; 124). In addition, the lipid kinase that phosphorylates PI(3)P to generate PI(3,5)P2 on endomembranes, PIKFYVE (a phosphatidylinositol-3-phosphate-5-kinase), controls mTORC1 activation in both mammalian cells and yeast, indicating an evolutionarily conserved function for this signaling lipid (124; 125). Moreover, PI(3,5)P2 binds to raptor, and in response to insulin in 3T3-L1 adipocytes, generation of PI(3,5)P2 contributes to mTORC1 activation and mediates mTORC1 translocation to the plasma membrane (124).…”

Section: The Lysosome As a Critical Platform For Upstream Signal Intementioning

confidence: 99%

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Growing knowledge of the mTOR signaling network

Huang

Fingar

2014

Seminars in Cell & Developmental Biology

274

256

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The kinase mTOR (mechanistic target of rapamycin) integrates diverse environmental signals and translates these cues into appropriate cellular responses. mTOR forms the catalytic core of at least two functionally distinct signaling complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). mTORC1 promotes anabolic cellular metabolism in response to growth factors, nutrients, and energy and functions as a master controller of cell growth. While significantly less well understood than mTORC1, mTORC2 responds to growth factors and controls cell metabolism, cell survival, and the organization of the actin cytoskeleton. mTOR plays critical roles in cellular processes related to tumorigenesis, metabolism, immune function, and aging. Consequently, aberrant mTOR signaling contributes to myriad disease states, and physicians employ mTORC1 inhibitors (rapamycin and analogs) for several pathological conditions. The clinical utility of mTOR inhibition underscores the important role of mTOR in organismal physiology. Here we review our growing knowledge of cellular mTOR regulation by diverse upstream signals (e.g. growth factors; amino acids; energy) and how mTORC1 integrates these signals to effect appropriate downstream signaling, with a greater emphasis on mTORC1 over mTORC2. We highlight dynamic subcellular localization of mTORC1 and associated factors as an important mechanism for control of mTORC1 activity and function. We will cover major cellular functions controlled by mTORC1 broadly. While significant advances have been made in the last decade regarding the regulation and function of mTOR within complex cell signaling networks, many important findings remain to be discovered.

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Section: The Lysosome As a Critical Platform For Upstream Signal Intementioning

confidence: 73%

Section: Future Directionsmentioning

confidence: 94%

Section: The Lysosome As a Critical Platform For Upstream Signal Intementioning

confidence: 99%

See 1 more Smart Citation

Growing knowledge of the mTOR signaling network

Huang

Fingar

2014

Seminars in Cell & Developmental Biology

274

256

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“…There was a report that PI 3,5-bisphosphate [PI(3,5)P2] directly binds to Kog1 and Sch9 and is necessary for the intact vacuolar localization of Kog1 and Sch9 (36). Therefore, we tested whether PI(3,5)P2 is necessary for TORC1 glutamine responsiveness in vitro.…”

Section: Discussionmentioning

confidence: 99%

An In Vitro TORC1 Kinase Assay That Recapitulates the Gtr-Independent Glutamine-Responsive TORC1 Activation Mechanism on Yeast Vacuoles

Tanigawa

Maeda

2017

Molecular and Cellular Biology

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Evolutionarily conserved target of rapamycin (TOR) complex 1 (TORC1) responds to nutrients, especially amino acids, to promote cell growth. In the yeast Saccharomyces cerevisiae, various nitrogen sources activate TORC1 with different efficiencies, although the mechanism remains elusive. Leucine, and perhaps other amino acids, was reported to activate TORC1 via the heterodimeric small GTPases Gtr1-Gtr2, the orthologues of the mammalian Rag GTPases. More recently, an alternative Gtr-independent TORC1 activation mechanism that may respond to glutamine was reported, although its molecular mechanism is not clear. In studying the nutrient-responsive TORC1 activation mechanism, the lack of an in vitro assay hinders associating particular nutrient compounds with the TORC1 activation status, whereas no in vitro assay that shows nutrient responsiveness has been reported. In this study, we have developed a new in vitro TORC1 kinase assay that reproduces, for the first time, the nutrient-responsive TORC1 activation. This in vitro TORC1 assay recapitulates the previously predicted Gtr-independent glutamine-responsive TORC1 activation mechanism. Using this system, we found that this mechanism specifically responds to L-glutamine, resides on the vacuolar membranes, and involves a previously uncharacterized Vps34-Vps15 phosphatidylinositol (PI) 3-kinase complex and the PI-3-phosphate [PI(3)P]-binding FYVE domain-containing vacuolar protein Pib2. Thus, this system was proved to be useful for dissecting the glutamine-responsive TORC1 activation mechanism.KEYWORDS Saccharomyces cerevisiae, TOR kinase, TORC1, Vps34, glutamine, in vitro kinase assay T he target of rapamycin (TOR) is an evolutionarily conserved protein kinase that regulates cell growth as the catalytic component of rapamycin-sensitive TOR complex 1 (TORC1) (1, 2). TORC1 is activated by nutrients, particularly amino acids, in all tested eukaryotes, and active TORC1 promotes cell growth by activating anabolic processes, including synthesis of protein, lipids, and nucleotides and by inhibiting catabolic processes, such as autophagy. In mammals, TORC1 consists of mammalian/ mechanistic TOR (mTOR), raptor, mammalian Lst8 (mLst8), DEP domain-containing mTOR-interacting protein (DEPTOR), and PRAS40, whereas in the yeast Saccharomyces cerevisiae, TORC1 consists of Tor1 or Tor2, the raptor orthologue Kog1, the mLst8 orthologue Lst8, and Tco89. Recent studies have revealed an evolutionarily conserved amino acid-responsive TORC1 activation mechanism, in which heterodimeric small GTPases, RagA or RagB (RagA/B)-RagC/D in mammals and Gtr1-Gtr2 in yeast, play a central role (3)(4)(5). The mammalian Rag heterodimer is anchored to the lysosomal membrane through the Ragulator complex. An amino acid stimulus induces conversion of RagA/B from the GDP-bound state to the GTP-bound state, and the GTP-bound form directly binds to TORC1 (3, 4), thereby recruiting TORC1 to the lysosomal membrane Citation Tanigawa M, Maeda T. 2017. An in vitro TORC1 kinase assay that recapitulates the...

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“…A decrease of PI(3,5)P 2 levels in yeast causes defects in vacuolar degradation of autophagosomes that are delivered to the vacuole lumen [41]. Second, inhibition of Fab1 activity causes a loss of TORC1 activity and a concomitant increase in autophagy (discussed in below) [41]. These observations suggest that autophagy is a downstream pathway of PI(3,5)P 2 .…”

Section: The Pi(3)p 5-kinase Fab1/pikfyve Functions Within a Regulatomentioning

confidence: 99%

Phosphatidylinositol 3,5-bisphosphate: regulation of cellular events in space and time

Jin

Lang

Weisman

2016

Biochemical Society Transactions

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Phosphorylated phosphatidylinositol lipids are crucial for most eukaryotes and have diverse cellular functions. The low-abundance signaling lipid phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) is critical for cellular homeostasis and adaptation to stimuli. A large complex of proteins that includes the lipid kinase Fab1/PIKfyve, dynamically regulates the levels of PI(3,5)P2. Deficiencies in PI(3,5)P2 are linked to some human diseases, especially those of the nervous system. Future studies will likely determine new, undiscovered regulatory roles of PI(3,5)P2, as well as uncover mechanistic insights into how PI(3,5)P2 contributes to normal human physiology.

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Roles for PI(3,5)P₂ in nutrient sensing through TORC1

Cited by 78 publications

References 85 publications

Growing knowledge of the mTOR signaling network

Growing knowledge of the mTOR signaling network

An In Vitro TORC1 Kinase Assay That Recapitulates the Gtr-Independent Glutamine-Responsive TORC1 Activation Mechanism on Yeast Vacuoles

Phosphatidylinositol 3,5-bisphosphate: regulation of cellular events in space and time

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Roles for PI(3,5)P2 in nutrient sensing through TORC1

Cited by 78 publications

References 85 publications

Growing knowledge of the mTOR signaling network

Growing knowledge of the mTOR signaling network

An In Vitro TORC1 Kinase Assay That Recapitulates the Gtr-Independent Glutamine-Responsive TORC1 Activation Mechanism on Yeast Vacuoles

Phosphatidylinositol 3,5-bisphosphate: regulation of cellular events in space and time

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Roles for PI(3,5)P₂ in nutrient sensing through TORC1