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 Ca(2+)/calmodulin-dependent protein kinase kinase $\beta$ (CaMKK$\beta$). 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.
%0 Journal Article
%1 dallepezzeSystemsStudyReveals2016a
%A Dalle Pezze, Piero
%A Ruf, Stefanie
%A Sonntag, Annika G.
%A Langelaar-Makkinje, Miriam
%A Hall, Philip
%A Heberle, Alexander M.
%A Razquin Navas, Patricia
%A van Eunen, Karen
%A Tölle, Regine C.
%A Schwarz, Jennifer J.
%A Wiese, Heike
%A Warscheid, Bettina
%A Deitersen, Jana
%A Stork, Björn
%A Fäßler, Erik
%A Schäuble, Sascha
%A Hahn, Udo
%A Horvatovich, Peter
%A Shanley, Daryl P.
%A Thedieck, Kathrin
%C England
%D 2016
%J Nature communications
%K 1/genetics/*metabolism,Mechanistic 2/genetics/*metabolism,Models 3-Kinases/genetics/metabolism,Proto-Oncogene Acids/*pharmacology,AMP-Activated Amino Biological,Phosphatidylinositol Complex Expression Homolog/genetics/metabolism,Calcium-Calmodulin-Dependent Kinase Kinase/metabolism,Cell Kinases/genetics/*metabolism Kinases/genetics/*metabolism,Autophagy-Related Line,Gene Peptides Protein Protein-1 Proteins Proteins/genetics/metabolism,Mechanistic Rapamycin Regulation/drug Serine-Threonine Signaling Target and c-akt/genetics/metabolism,to_read,TOR effects,Humans,Intracellular of
%P 13254
%R 10.1038/ncomms13254
%T A Systems Study Reveals Concurrent Activation of AMPK and mTOR by Amino Acids.
%V 7
%X 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 Ca(2+)/calmodulin-dependent protein kinase kinase $\beta$ (CaMKK$\beta$). 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.
@article{dallepezzeSystemsStudyReveals2016a,
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 Ca(2+)/calmodulin-dependent protein kinase kinase {$\beta$} (CaMKK{$\beta$}). 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.},
added-at = {2024-05-17T13:01:35.000+0200},
address = {England},
author = {Dalle Pezze, Piero and Ruf, Stefanie and Sonntag, Annika G. and {Langelaar-Makkinje}, Miriam and Hall, Philip and Heberle, Alexander M. and Razquin Navas, Patricia and {van Eunen}, Karen and T{\"o}lle, Regine C. and Schwarz, Jennifer J. and Wiese, Heike and Warscheid, Bettina and Deitersen, Jana and Stork, Bj{\"o}rn and F{\"a}{\ss}ler, Erik and Sch{\"a}uble, Sascha and Hahn, Udo and Horvatovich, Peter and Shanley, Daryl P. and Thedieck, Kathrin},
biburl = {https://www.bibsonomy.org/bibtex/233a364fe6b55b46f87e99ab64873beaa/warscheidlab},
doi = {10.1038/ncomms13254},
interhash = {26373937450ca770daefd83028ddfdcd},
intrahash = {33a364fe6b55b46f87e99ab64873beaa},
issn = {2041-1723},
journal = {Nature communications},
keywords = {1/genetics/*metabolism,Mechanistic 2/genetics/*metabolism,Models 3-Kinases/genetics/metabolism,Proto-Oncogene Acids/*pharmacology,AMP-Activated Amino Biological,Phosphatidylinositol Complex Expression Homolog/genetics/metabolism,Calcium-Calmodulin-Dependent Kinase Kinase/metabolism,Cell Kinases/genetics/*metabolism Kinases/genetics/*metabolism,Autophagy-Related Line,Gene Peptides Protein Protein-1 Proteins Proteins/genetics/metabolism,Mechanistic Rapamycin Regulation/drug Serine-Threonine Signaling Target and c-akt/genetics/metabolism,to_read,TOR effects,Humans,Intracellular of},
langid = {english},
month = nov,
pages = 13254,
pmcid = {PMC5121333},
pmid = {27869123},
timestamp = {2024-05-17T13:01:35.000+0200},
title = {A Systems Study Reveals Concurrent Activation of {{AMPK}} and {{mTOR}} by Amino Acids.},
volume = 7,
year = 2016
}