A systems study reveals concurrent activation of AMPK and mTOR by amino acids
Ontology highlight
ABSTRACT:
OTHER RELATED OMICS DATASETS IN: BIOMD0000000640
INSTRUMENT(S): LTQ Orbitrap XL
ORGANISM(S): Mus Musculus (mouse)
TISSUE(S): Myoblast
SUBMITTER: 
Horvatovich Péter
LAB HEAD: Kathrin Thedieck
PROVIDER: PXD003073 | Pride | 2016-12-12
REPOSITORIES: Pride
Publications
A systems study reveals concurrent activation of AMPK and mTOR by amino acids.
Dalle Pezze Piero P Ruf Stefanie S Sonntag Annika G AG Langelaar-Makkinje Miriam M Hall Philip P Heberle Alexander M AM Razquin Navas Patricia P van Eunen Karen K Tölle Regine C RC Schwarz Jennifer J JJ Wiese Heike H Warscheid Bettina B Deitersen Jana J Stork Björn B Fäßler Erik E Schäuble Sascha S Hahn Udo U Horvatovich Peter P Shanley Daryl P DP Thedieck Kathrin K
Nature communications 20161121
Amino acids (aa) are not only building blocks for proteins, but also signalling molecules, with the mammalian target of rapamycin complex 1 (mTORC1) acting as a key mediator. However, little is known about whether aa, independently of mTORC1, activate other kinases of the mTOR signalling network. To delineate aa-stimulated mTOR network dynamics, we here combine a computational-experimental approach with text mining-enhanced quantitative proteomics. We report that AMP-activated protein kinase (AM ...[more]
Similar Datasets
Project description:DallePezze2016 - Activation of AMPK and mTOR
by amino acids (Model 1)
This model is as described in
Supplementary Software 2 of the reference publication:
SBML
model including only the canonical amino acid input on
mTORC1.
This model is described in the article:
A systems study reveals
concurrent activation of AMPK and mTOR by amino acids.
Dalle Pezze P, Ruf S, Sonntag AG,
Langelaar-Makkinje M, Hall P, Heberle AM, Razquin Navas P, van
Eunen K, Tölle RC, Schwarz JJ, Wiese H, Warscheid B,
Deitersen J, Stork B, Fäßler E, Schäuble S, Hahn
U, Horvatovich P, Shanley DP, Thedieck K.
Nat Commun 2016 Nov; 7: 13254
Abstract:
Amino acids (aa) are not only building blocks for proteins,
but also signalling molecules, with the mammalian target of
rapamycin complex 1 (mTORC1) acting as a key mediator. However,
little is known about whether aa, independently of mTORC1,
activate other kinases of the mTOR signalling network. To
delineate aa-stimulated mTOR network dynamics, we here combine
a computational-experimental approach with text mining-enhanced
quantitative proteomics. We report that AMP-activated protein
kinase (AMPK), phosphatidylinositide 3-kinase (PI3K) and mTOR
complex 2 (mTORC2) are acutely activated by aa-readdition in an
mTORC1-independent manner. AMPK activation by aa is mediated by
Ca2+/calmodulin-dependent protein kinase kinase ? (CaMKK?). In
response, AMPK impinges on the autophagy regulators Unc-51-like
kinase-1 (ULK1) and c-Jun. AMPK is widely recognized as an
mTORC1 antagonist that is activated by starvation. We find that
aa acutely activate AMPK concurrently with mTOR. We show that
AMPK under aa sufficiency acts to sustain autophagy. This may
be required to maintain protein homoeostasis and deliver
metabolite intermediates for biosynthetic processes.
This model is hosted on
BioModels Database
and identified by:
MODEL1705030000.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2017-05-18 | MODEL1705030000 | BioModels
Project description:DallePezze2016 - Activation of AMPK and mTOR
by amino acids (Model 2)
This
model is as described in the Supplementary Software 2 of the
reference publication:
SBML
model including four amino acids input in the network (simple
p70-S6K module).
This model is described in the article:
A systems study reveals
concurrent activation of AMPK and mTOR by amino acids.
Dalle Pezze P, Ruf S, Sonntag AG,
Langelaar-Makkinje M, Hall P, Heberle AM, Razquin Navas P, van
Eunen K, Tölle RC, Schwarz JJ, Wiese H, Warscheid B,
Deitersen J, Stork B, Fäßler E, Schäuble S, Hahn
U, Horvatovich P, Shanley DP, Thedieck K.
Nat Commun 2016 Nov; 7: 13254
Abstract:
Amino acids (aa) are not only building blocks for proteins,
but also signalling molecules, with the mammalian target of
rapamycin complex 1 (mTORC1) acting as a key mediator. However,
little is known about whether aa, independently of mTORC1,
activate other kinases of the mTOR signalling network. To
delineate aa-stimulated mTOR network dynamics, we here combine
a computational-experimental approach with text mining-enhanced
quantitative proteomics. We report that AMP-activated protein
kinase (AMPK), phosphatidylinositide 3-kinase (PI3K) and mTOR
complex 2 (mTORC2) are acutely activated by aa-readdition in an
mTORC1-independent manner. AMPK activation by aa is mediated by
Ca2+/calmodulin-dependent protein kinase kinase ? (CaMKK?). In
response, AMPK impinges on the autophagy regulators Unc-51-like
kinase-1 (ULK1) and c-Jun. AMPK is widely recognized as an
mTORC1 antagonist that is activated by starvation. We find that
aa acutely activate AMPK concurrently with mTOR. We show that
AMPK under aa sufficiency acts to sustain autophagy. This may
be required to maintain protein homoeostasis and deliver
metabolite intermediates for biosynthetic processes.
This model is hosted on
BioModels Database
and identified by:
MODEL1705030001.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2017-05-18 | MODEL1705030001 | BioModels
Project description:DallePezze2016 - Activation of AMPK and mTOR
by amino acids (Model 3)
This model is as described in
the Supplementary Software 3 of the reference publication: SBML
model similar to Model S2, but including a more complex p70-S6K
module.
This model is described in the article:
A systems study reveals
concurrent activation of AMPK and mTOR by amino acids.
Dalle Pezze P, Ruf S, Sonntag AG,
Langelaar-Makkinje M, Hall P, Heberle AM, Razquin Navas P, van
Eunen K, Tölle RC, Schwarz JJ, Wiese H, Warscheid B,
Deitersen J, Stork B, Fäßler E, Schäuble S, Hahn
U, Horvatovich P, Shanley DP, Thedieck K.
Nat Commun 2016 Nov; 7: 13254
Abstract:
Amino acids (aa) are not only building blocks for proteins,
but also signalling molecules, with the mammalian target of
rapamycin complex 1 (mTORC1) acting as a key mediator. However,
little is known about whether aa, independently of mTORC1,
activate other kinases of the mTOR signalling network. To
delineate aa-stimulated mTOR network dynamics, we here combine
a computational-experimental approach with text mining-enhanced
quantitative proteomics. We report that AMP-activated protein
kinase (AMPK), phosphatidylinositide 3-kinase (PI3K) and mTOR
complex 2 (mTORC2) are acutely activated by aa-readdition in an
mTORC1-independent manner. AMPK activation by aa is mediated by
Ca2+/calmodulin-dependent protein kinase kinase ? (CaMKK?). In
response, AMPK impinges on the autophagy regulators Unc-51-like
kinase-1 (ULK1) and c-Jun. AMPK is widely recognized as an
mTORC1 antagonist that is activated by starvation. We find that
aa acutely activate AMPK concurrently with mTOR. We show that
AMPK under aa sufficiency acts to sustain autophagy. This may
be required to maintain protein homoeostasis and deliver
metabolite intermediates for biosynthetic processes.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000640.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2015-05-07 | BIOMD0000000640 | BioModels
Project description:Sonntag2012 - mTOR model - IRS dependent regulation of AMPK by insulin
TSC1-TSC2 complex has two states: 1)
active (TSC1_TSC2_pS1387), regulated by AMPK_pT172; 2) inactive
(TSC1_TSC2_pT1462) regulated by Akt_pT308. Particularly, mTORC1 is
inhibited by TSC1_TSC2 in active state. AMPK is activated at T172
by the species IRS1_p activated by the insulin receptor upon
insulin stimulation. Consequently, AMPK_pT172 is inhibited by
mTORC1_pS2448 indirectly by the p70-S6K-negative feedback loop.
This model is described in the article:
A modelling-experimental
approach reveals insulin receptor substrate (IRS)-dependent
regulation of adenosine monosphosphate-dependent kinase (AMPK)
by insulin.
Sonntag AG, Dalle Pezze P, Shanley
DP, Thedieck K.
FEBS J. 2012 Sep; 279(18):
3314-3328
Abstract:
Mammalian target of rapamycin (mTOR) kinase responds to
growth factors, nutrients and cellular energy status and is a
central controller of cellular growth. mTOR exists in two
multiprotein complexes that are embedded into a complex
signalling network. Adenosine monophosphate-dependent kinase
(AMPK) is activated by energy deprivation and shuts off
adenosine 5'-triphosphate (ATP)-consuming anabolic processes,
in part via the inactivation of mTORC1. Surprisingly, we
observed that AMPK not only responds to energy deprivation but
can also be activated by insulin, and is further induced in
mTORC1-deficient cells. We have recently modelled the mTOR
network, covering both mTOR complexes and their insulin and
nutrient inputs. In the present study we extended the network
by an AMPK module to generate the to date most comprehensive
data-driven dynamic AMPK-mTOR network model. In order to define
the intersection via which AMPK is activated by the insulin
network, we compared simulations for six different hypothetical
model structures to our observed AMPK dynamics. Hypotheses
ranking suggested that the most probable intersection between
insulin and AMPK was the insulin receptor substrate (IRS) and
that the effects of canonical IRS downstream cues on AMPK would
be mediated via an mTORC1-driven negative-feedback loop. We
tested these predictions experimentally in multiple set-ups,
where we inhibited or induced players along the insulin-mTORC1
signalling axis and observed AMPK induction or inhibition. We
confirmed the identified model and therefore report a novel
connection within the insulin-mTOR-AMPK network: we conclude
that AMPK is positively regulated by IRS and can be inhibited
via the negative-feedback loop.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000580.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2015-08-12 | BIOMD0000000580 | BioModels
Project description:The serine/threonine kinase mammalian target of rapamycin (mTOR) governs growth, metabolism, and aging in response to insulin and amino acids (aa), and is often activated in metabolic disorders and cancer. Much is known about the regulatory signaling network around mTOR, but surprisingly few direct mTOR substrates have been established to date. To tackle this gap in our knowledge, we took advantage of a combined quantitative phosphoproteomic and interactomic strategy. We analyzed the insulin- and aa-responsive phosphoproteome upon inhibition of the mTOR complex 1 (mTORC1) component raptor, and analyzed in parallel the interactome of endogenous mTOR. By overlaying these two datasets, we identified acinus L as a potential novel mTORC1 target. We confirmed acinus L as a direct mTORC1 substrate by co-immunoprecipitation and MS-enhanced kinase assays. Our study delineates a triple proteomics strategy of combined phosphoproteomics, interactomics, and MS-enhanced kinase assays for the de novo-identification of mTOR network components, and provides a rich source of potential novel mTOR interactors and targets for future investigation.<br><br>Additional contact details:<br><a href="mailto:k.thedieck@umcg.nl">Prof. Dr. Kathrin Thedieck</a><br>Department of Pediatrics, University of Groningen, University Medical Center Groningen (UMCG), 9713 AV Groningen, The Netherlands.<br>Faculty VI - School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, 26111 Oldenburg, Germany.<br><br>Prof. Dr. Bettina Warscheid<br>Faculty of Biology, Institute of Biology II, University of Freiburg, 79104 Freiburg, Germany.<br>BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany.<br>
2015-04-28 | PXD001244 | Pride
Project description:The serine/threonine kinase mammalian target of rapamycin (mTOR) governs growth, metabolism, and aging in response to insulin and amino acids (aa), and is often activated in metabolic disorders and cancer. Much is known about the regulatory signaling network around mTOR, but surprisingly few direct mTOR substrates have been established to date. To tackle this gap in our knowledge, we took advantage of a combined quantitative phosphoproteomic and interactomic strategy. We analyzed the insulin- and aa-responsive phosphoproteome upon inhibition of the mTOR complex 1 (mTORC1) component raptor, and analyzed in parallel the interactome of endogenous mTOR. By overlaying these two datasets, we identified acinus L as a potential novel mTORC1 target. We confirmed acinus L as a direct mTORC1 substrate by co-immunoprecipitation and MS-enhanced kinase assays. Our study delineates a triple proteomics strategy of combined phosphoproteomics, interactomics, and MS-enhanced kinase assays for the de novo-identification of mTOR network components, and provides a rich source of potential novel mTOR interactors and targets for future investigation.<br><br>Additional contact details:<br><a href="mailto:k.thedieck@umcg.nl">Prof. Dr. Kathrin Thedieck</a><br>Department of Pediatrics, University of Groningen, University Medical Center Groningen (UMCG), 9713 AV Groningen, The Netherlands.<br>Faculty VI - School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, 26111 Oldenburg, Germany.<br><br>Prof. Dr. Bettina Warscheid<br>Faculty of Biology, Institute of Biology II, University of Freiburg, 79104 Freiburg, Germany.<br>BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany.<br>
2015-04-28 | PXD001196 | Pride
Project description:The serine/threonine kinase mammalian target of rapamycin (mTOR) governs growth, metabolism, and aging in response to insulin and amino acids (aa), and is often activated in metabolic disorders and cancer. Much is known about the regulatory signaling network around mTOR, but surprisingly few direct mTOR substrates have been established to date. To tackle this gap in our knowledge, we took advantage of a combined quantitative phosphoproteomic and interactomic strategy. We analyzed the insulin- and aa-responsive phosphoproteome upon inhibition of the mTOR complex 1 (mTORC1) component raptor, and analyzed in parallel the interactome of endogenous mTOR. By overlaying these two datasets, we identified acinus L as a potential novel mTORC1 target. We confirmed acinus L as a direct mTORC1 substrate by co-immunoprecipitation and MS-enhanced kinase assays. Our study delineates a triple proteomics strategy of combined phosphoproteomics, interactomics, and MS-enhanced kinase assays for the de novo-identification of mTOR network components, and provides a rich source of potential novel mTOR interactors and targets for future investigation.<br><br>Additional contact details:<br><a href="mailto:k.thedieck@umcg.nl">Prof. Dr. Kathrin Thedieck</a><br>Department of Pediatrics, University of Groningen, University Medical Center Groningen (UMCG), 9713 AV Groningen, The Netherlands.<br>Faculty VI - School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, 26111 Oldenburg, Germany.<br><br>Prof. Dr. Bettina Warscheid<br>Faculty of Biology, Institute of Biology II, University of Freiburg, 79104 Freiburg, Germany.<br>BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany.<br>
2015-04-28 | PXD001245 | Pride
Project description:Cells respond to mitochondrial energetic stress with rapid activation of the AMP-activated protein kinase (AMPK), which acutely inhibits anabolism and stimulates catabolism. AMPK also induces sustained transcriptional reprogramming of metabolism. The TFEB transcription factor is a major effector of AMPK signals, inducing lysosome genes following energetic stress. Yet the molecular mechanism underlying how AMPK activates TFEB remains unresolved. We demonstrate here that AMPK directly phosphorylates five conserved serine residues in FNIP1, which suppresses the function of the FLCN/FNIP1 RagC GAP complex, in turn controlling TFEB lysosomal localization. We demonstrate that FNIP1 phosphorylation is required for AMPK to induce nuclear translocation of TFEB, which is fully separable from AMPK control of canonical mTORC1 signaling. Using a non-phosphorylatable allele of FNIP1, we show that in parallel to lysosomal biogenesis, AMPK induces mitochondrial biogenesis via TFEB-dependent induction of PGC1a mRNA. This signaling from mitochondrial stress is also independent of amino-acid control of the Rags and TFEB, which still proceed normally in cells bearing the AMPK-non phosphorylatable allele of FNIP1. Taken together, mitochondrial energetic stress triggers AMPK/FNIP1-dependent TFEB nuclear translocation, inducing transcriptional waves of lysosomal and mitochondrial biogenesis.
2023-05-08 | GSE218827 | GEO
Project description:Despite being the frontline therapy for Type 2 diabetes, the mechanisms of action of the biguanide drug metformin are still being discovered. In particular, the detailed molecular interplays between the AMPK and the mTORC1 pathway in the hepatic benefits of metformin are still ill-defined. Metformin-dependent activation of AMPK classically inhibits mTORC1 via TSC/RHEB. But several lines of evidence suggest additional mechanisms at play in metformin inhibition of mTORC1. Here we investigated the role of direct AMPK-mediated serine phosphorylation of RAPTOR in a new RaptorAA mouse model, in which AMPK phospho-serine sites Ser722 and Ser792 of RAPTOR were mutated to alanine. Metformin treatment of intact murine liver requires AMPK regulation of both RAPTOR and TSC2 to fully inhibit mTORC1, and this regulation is critical for the transcriptional response to metformin. Transcriptionally, AMPK and mTORC1 were both important for regulation of anabolic metabolism and inflammatory programs triggered by metformin treatment. The hepatic transcriptional response in mice on high fat diet treated with metformin was largely ablated by AMPK-deficiency under the conditions examined, indicating the essential role of this kinase and its targets in metformin action in vivo.
2023-08-10 | GSE157049 | GEO
Project description:The mammalian target of rapamycin (mTOR) is a central regulator of cell growth and proliferation in response to growth factor and nutrient signaling. Consequently, this kinase is implicated in metabolic diseases including cancer and diabetes so there is great interest in understanding mTOR regulatory networks. mTOR exists in two functionally distinct complexes, mTORC1 and mTORC2, and whereas the natural product rapamycin only inhibits a subset of mTORC1 functions, recently developed ATP-competitive mTOR inhibitors have revealed new roles for both complexes. To examine the complete spectrum of mTOR responsive cellular processes, we compared the transcriptional profiles of mammalian cells treated with rapamycin versus the ATP-competitive inhibitor PP242. Our analysis provides a genome-wide view of the transcriptional outputs of mTOR signaling that are insensitive to rapamycin. Gene expression in mouse NIH3T3 cells was measured after 18 hour treatment with DMSO (control), 50 nM rapamycin, or 2 uM PP242. Four independent experiments were performed for each condition.
2011-03-15 | E-GEOD-27784 | biostudies-arrayexpress