Evidence map›Paper›PMID 25761126›Full record

ArticlePloS one2015

Computational analysis of an autophagy/translation switch based on mutual inhibition of MTORC1 and ULK1.

Paulina Szymańska, Katie R Martin, Jeffrey P MacKeigan, William S Hlavacek, Tomasz Lipniacki

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in PloS one, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
29citing papers in PubMed, 1 pooled it
3.1field-weighted citation impact, top 8% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

29 citing papers in PubMed, 1 synthesis or guideline pooled it, 44 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

5 authors at 4 institutions in 2 countries.

Paulina SzymańskaCollege of Inter-Faculty Individual Studies in Mathematics and Natural Sciences, University of Warsaw, Warsaw, Poland.
Katie R MartinVan Andel Institute, Grand Rapids, Michigan, United States of America.
Jeffrey P MacKeiganVan Andel Institute, Grand Rapids, Michigan, United States of America.
William S HlavacekTheoretical Division and Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.
Tomasz LipniackiInstitute of Fundamental Technological Research, Warsaw, Poland.
Van Andel Institute · USInstitute of Fundamental Technological Research · PLLos Alamos National Laboratory · USUniversity of Warsaw · PL

Funding

UNM TRAININGP50GM085273 · NIGMS · UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR · PI EDWARDS, JEREMY S · 2009 to 2018
$26.1M
NIGMS NIH HHS P50 GM085273NIGMS NIH HHS P50GM085273
6 · The paper itself

Abstract

We constructed a mechanistic, computational model for regulation of (macro)autophagy and protein synthesis (at the level of translation). The model was formulated to study the system-level consequences of interactions among the following proteins: two key components of MTOR complex 1 (MTORC1), namely the protein kinase MTOR (mechanistic target of rapamycin) and the scaffold protein RPTOR; the autophagy-initiating protein kinase ULK1; and the multimeric energy-sensing AMP-activated protein kinase (AMPK). Inputs of the model include intrinsic AMPK kinase activity, which is taken as an adjustable surrogate parameter for cellular energy level or AMP:ATP ratio, and rapamycin dose, which controls MTORC1 activity. Outputs of the model include the phosphorylation level of the translational repressor EIF4EBP1, a substrate of MTORC1, and the phosphorylation level of AMBRA1 (activating molecule in BECN1-regulated autophagy), a substrate of ULK1 critical for autophagosome formation. The model incorporates reciprocal regulation of mTORC1 and ULK1 by AMPK, mutual inhibition of MTORC1 and ULK1, and ULK1-mediated negative feedback regulation of AMPK. Through analysis of the model, we find that these processes may be responsible, depending on conditions, for graded responses to stress inputs, for bistable switching between autophagy and protein synthesis, or relaxation oscillations, comprising alternating periods of autophagy and protein synthesis. A sensitivity analysis indicates that the prediction of oscillatory behavior is robust to changes of the parameter values of the model. The model provides testable predictions about the behavior of the AMPK-MTORC1-ULK1 network, which plays a central role in maintaining cellular energy and nutrient homeostasis.

Indexed as

Protein BiosynthesisAdaptor Proteins, Signal TransducingAMP-Activated Protein KinasesAutophagyAutophagy-Related Protein-1 HomologCell Cycle ProteinsComputational BiologyGene Expression RegulationHumansIntracellular Signaling Peptides and ProteinsMechanistic Target of Rapamycin Complex 1Models, GeneticMultiprotein ComplexesPhosphoproteinsProtein Serine-Threonine KinasesSirolimusAdaptor Proteins, Signal TransducingAMBRA1 protein, humanAMP-Activated Protein KinasesAutophagy-Related Protein-1 HomologCell Cycle ProteinsEIF4EBP1 protein, humanIntracellular Signaling Peptides and ProteinsMechanistic Target of Rapamycin Complex 1Multiprotein ComplexesPhosphoproteinsProtein Serine-Threonine KinasesSirolimusTOR Serine-Threonine KinasesULK1 protein, human

Identifiers

PMID25761126
PMCPMC4356596
OpenAlexW2037643541

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.