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MAP4K3 inhibits Sirtuin-1 to repress the LKB1–AMPK pathway to promote amino acid-dependent activation of the mTORC1 complex

mTORC1 is the key rheostat controlling the cellular metabolic state. Of the various inputs to mTORC1, the most potent effector of intracellular nutrient status is amino acid supply. Despite an established role for MAP4K3 in promoting mTORC1 activation in the presence of amino acids, the signaling pa...

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Autores principales: Branch, Mary Rose, Hsu, Cynthia L, Ohnishi, Kohta, Shen, Wen-Chuan, Lee, Elian, Meisenhelder, Jill, Winborn, Brett, Sopher, Bryce L, Taylor, J Paul, Hunter, Tony, La Spada, Albert R
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Life Science Alliance LLC 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10205607/
https://www.ncbi.nlm.nih.gov/pubmed/37221017
http://dx.doi.org/10.26508/lsa.202201525
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author Branch, Mary Rose
Hsu, Cynthia L
Ohnishi, Kohta
Shen, Wen-Chuan
Lee, Elian
Meisenhelder, Jill
Winborn, Brett
Sopher, Bryce L
Taylor, J Paul
Hunter, Tony
La Spada, Albert R
author_facet Branch, Mary Rose
Hsu, Cynthia L
Ohnishi, Kohta
Shen, Wen-Chuan
Lee, Elian
Meisenhelder, Jill
Winborn, Brett
Sopher, Bryce L
Taylor, J Paul
Hunter, Tony
La Spada, Albert R
author_sort Branch, Mary Rose
collection PubMed
description mTORC1 is the key rheostat controlling the cellular metabolic state. Of the various inputs to mTORC1, the most potent effector of intracellular nutrient status is amino acid supply. Despite an established role for MAP4K3 in promoting mTORC1 activation in the presence of amino acids, the signaling pathway by which MAP4K3 controls mTORC1 activation remains unknown. Here, we examined the process of MAP4K3 regulation of mTORC1 and found that MAP4K3 represses the LKB1–AMPK pathway to achieve robust mTORC1 activation. When we sought the regulatory link between MAP4K3 and LKB1 inhibition, we discovered that MAP4K3 physically interacts with the master nutrient regulatory factor sirtuin-1 (SIRT1) and phosphorylates SIRT1 to repress LKB1 activation. Our results reveal the existence of a novel signaling pathway linking amino acid satiety with MAP4K3-dependent suppression of SIRT1 to inactivate the repressive LKB1–AMPK pathway and thereby potently activate the mTORC1 complex to dictate the metabolic disposition of the cell.
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spelling pubmed-102056072023-05-25 MAP4K3 inhibits Sirtuin-1 to repress the LKB1–AMPK pathway to promote amino acid-dependent activation of the mTORC1 complex Branch, Mary Rose Hsu, Cynthia L Ohnishi, Kohta Shen, Wen-Chuan Lee, Elian Meisenhelder, Jill Winborn, Brett Sopher, Bryce L Taylor, J Paul Hunter, Tony La Spada, Albert R Life Sci Alliance Research Articles mTORC1 is the key rheostat controlling the cellular metabolic state. Of the various inputs to mTORC1, the most potent effector of intracellular nutrient status is amino acid supply. Despite an established role for MAP4K3 in promoting mTORC1 activation in the presence of amino acids, the signaling pathway by which MAP4K3 controls mTORC1 activation remains unknown. Here, we examined the process of MAP4K3 regulation of mTORC1 and found that MAP4K3 represses the LKB1–AMPK pathway to achieve robust mTORC1 activation. When we sought the regulatory link between MAP4K3 and LKB1 inhibition, we discovered that MAP4K3 physically interacts with the master nutrient regulatory factor sirtuin-1 (SIRT1) and phosphorylates SIRT1 to repress LKB1 activation. Our results reveal the existence of a novel signaling pathway linking amino acid satiety with MAP4K3-dependent suppression of SIRT1 to inactivate the repressive LKB1–AMPK pathway and thereby potently activate the mTORC1 complex to dictate the metabolic disposition of the cell. Life Science Alliance LLC 2023-05-23 /pmc/articles/PMC10205607/ /pubmed/37221017 http://dx.doi.org/10.26508/lsa.202201525 Text en © 2023 Branch et al. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Articles
Branch, Mary Rose
Hsu, Cynthia L
Ohnishi, Kohta
Shen, Wen-Chuan
Lee, Elian
Meisenhelder, Jill
Winborn, Brett
Sopher, Bryce L
Taylor, J Paul
Hunter, Tony
La Spada, Albert R
MAP4K3 inhibits Sirtuin-1 to repress the LKB1–AMPK pathway to promote amino acid-dependent activation of the mTORC1 complex
title MAP4K3 inhibits Sirtuin-1 to repress the LKB1–AMPK pathway to promote amino acid-dependent activation of the mTORC1 complex
title_full MAP4K3 inhibits Sirtuin-1 to repress the LKB1–AMPK pathway to promote amino acid-dependent activation of the mTORC1 complex
title_fullStr MAP4K3 inhibits Sirtuin-1 to repress the LKB1–AMPK pathway to promote amino acid-dependent activation of the mTORC1 complex
title_full_unstemmed MAP4K3 inhibits Sirtuin-1 to repress the LKB1–AMPK pathway to promote amino acid-dependent activation of the mTORC1 complex
title_short MAP4K3 inhibits Sirtuin-1 to repress the LKB1–AMPK pathway to promote amino acid-dependent activation of the mTORC1 complex
title_sort map4k3 inhibits sirtuin-1 to repress the lkb1–ampk pathway to promote amino acid-dependent activation of the mtorc1 complex
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10205607/
https://www.ncbi.nlm.nih.gov/pubmed/37221017
http://dx.doi.org/10.26508/lsa.202201525
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