Inhibition of AMPK catabolic action by GSK3

Tsukasa Suzuki, Dave Bridges, Daisuke Nakada, Georgios Skiniotis, Sean J. Morrison, Jiandie D. Lin, Alan R. Saltiel, Ken Inoki

Research output: Contribution to journalArticle

92 Citations (Scopus)

Abstract

AMP-activated protein kinase (AMPK) regulates cellular energy homeostasis by inhibiting anabolic and activating catabolic processes. While AMPK activation has been extensively studied, mechanisms that inhibit AMPK remain elusive. Here we report that glycogen synthase kinase 3 (GSK3) inhibits AMPK function. GSK3 forms a stable complex with AMPK through interactions with the AMPK β regulatory subunit and phosphorylates the AMPK α catalytic subunit. This phosphorylation enhances the accessibility of the activation loop of the α subunit to phosphatases, thereby inhibiting AMPK kinase activity. Surprisingly, PI3K-Akt signaling, which is a major anabolic signaling and normally inhibits GSK3 activity, promotes GSK3 phosphorylation and inhibition of AMPK, thus revealing how AMPK senses anabolic environments in addition to cellular energy levels. Consistently, disrupting GSK3 function within the AMPK complex sustains higher AMPK activity and cellular catabolic processes even under anabolic conditions, indicating that GSK3 acts as a critical sensor for anabolic signaling to regulate AMPK.

Original languageEnglish (US)
Pages (from-to)407-419
Number of pages13
JournalMolecular Cell
Volume50
Issue number3
DOIs
StatePublished - May 9 2013

Fingerprint

Glycogen Synthase Kinase 3
AMP-Activated Protein Kinases
Phosphorylation
Phosphatidylinositol 3-Kinases
Phosphoric Monoester Hydrolases
Catalytic Domain
Homeostasis

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Suzuki, T., Bridges, D., Nakada, D., Skiniotis, G., Morrison, S. J., Lin, J. D., ... Inoki, K. (2013). Inhibition of AMPK catabolic action by GSK3. Molecular Cell, 50(3), 407-419. https://doi.org/10.1016/j.molcel.2013.03.022

Inhibition of AMPK catabolic action by GSK3. / Suzuki, Tsukasa; Bridges, Dave; Nakada, Daisuke; Skiniotis, Georgios; Morrison, Sean J.; Lin, Jiandie D.; Saltiel, Alan R.; Inoki, Ken.

In: Molecular Cell, Vol. 50, No. 3, 09.05.2013, p. 407-419.

Research output: Contribution to journalArticle

Suzuki, T, Bridges, D, Nakada, D, Skiniotis, G, Morrison, SJ, Lin, JD, Saltiel, AR & Inoki, K 2013, 'Inhibition of AMPK catabolic action by GSK3', Molecular Cell, vol. 50, no. 3, pp. 407-419. https://doi.org/10.1016/j.molcel.2013.03.022
Suzuki T, Bridges D, Nakada D, Skiniotis G, Morrison SJ, Lin JD et al. Inhibition of AMPK catabolic action by GSK3. Molecular Cell. 2013 May 9;50(3):407-419. https://doi.org/10.1016/j.molcel.2013.03.022
Suzuki, Tsukasa ; Bridges, Dave ; Nakada, Daisuke ; Skiniotis, Georgios ; Morrison, Sean J. ; Lin, Jiandie D. ; Saltiel, Alan R. ; Inoki, Ken. / Inhibition of AMPK catabolic action by GSK3. In: Molecular Cell. 2013 ; Vol. 50, No. 3. pp. 407-419.
@article{d9ef6e3deb61471382fc35d482e58d65,
title = "Inhibition of AMPK catabolic action by GSK3",
abstract = "AMP-activated protein kinase (AMPK) regulates cellular energy homeostasis by inhibiting anabolic and activating catabolic processes. While AMPK activation has been extensively studied, mechanisms that inhibit AMPK remain elusive. Here we report that glycogen synthase kinase 3 (GSK3) inhibits AMPK function. GSK3 forms a stable complex with AMPK through interactions with the AMPK β regulatory subunit and phosphorylates the AMPK α catalytic subunit. This phosphorylation enhances the accessibility of the activation loop of the α subunit to phosphatases, thereby inhibiting AMPK kinase activity. Surprisingly, PI3K-Akt signaling, which is a major anabolic signaling and normally inhibits GSK3 activity, promotes GSK3 phosphorylation and inhibition of AMPK, thus revealing how AMPK senses anabolic environments in addition to cellular energy levels. Consistently, disrupting GSK3 function within the AMPK complex sustains higher AMPK activity and cellular catabolic processes even under anabolic conditions, indicating that GSK3 acts as a critical sensor for anabolic signaling to regulate AMPK.",
author = "Tsukasa Suzuki and Dave Bridges and Daisuke Nakada and Georgios Skiniotis and Morrison, {Sean J.} and Lin, {Jiandie D.} and Saltiel, {Alan R.} and Ken Inoki",
year = "2013",
month = "5",
day = "9",
doi = "10.1016/j.molcel.2013.03.022",
language = "English (US)",
volume = "50",
pages = "407--419",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "3",

}

TY - JOUR

T1 - Inhibition of AMPK catabolic action by GSK3

AU - Suzuki, Tsukasa

AU - Bridges, Dave

AU - Nakada, Daisuke

AU - Skiniotis, Georgios

AU - Morrison, Sean J.

AU - Lin, Jiandie D.

AU - Saltiel, Alan R.

AU - Inoki, Ken

PY - 2013/5/9

Y1 - 2013/5/9

N2 - AMP-activated protein kinase (AMPK) regulates cellular energy homeostasis by inhibiting anabolic and activating catabolic processes. While AMPK activation has been extensively studied, mechanisms that inhibit AMPK remain elusive. Here we report that glycogen synthase kinase 3 (GSK3) inhibits AMPK function. GSK3 forms a stable complex with AMPK through interactions with the AMPK β regulatory subunit and phosphorylates the AMPK α catalytic subunit. This phosphorylation enhances the accessibility of the activation loop of the α subunit to phosphatases, thereby inhibiting AMPK kinase activity. Surprisingly, PI3K-Akt signaling, which is a major anabolic signaling and normally inhibits GSK3 activity, promotes GSK3 phosphorylation and inhibition of AMPK, thus revealing how AMPK senses anabolic environments in addition to cellular energy levels. Consistently, disrupting GSK3 function within the AMPK complex sustains higher AMPK activity and cellular catabolic processes even under anabolic conditions, indicating that GSK3 acts as a critical sensor for anabolic signaling to regulate AMPK.

AB - AMP-activated protein kinase (AMPK) regulates cellular energy homeostasis by inhibiting anabolic and activating catabolic processes. While AMPK activation has been extensively studied, mechanisms that inhibit AMPK remain elusive. Here we report that glycogen synthase kinase 3 (GSK3) inhibits AMPK function. GSK3 forms a stable complex with AMPK through interactions with the AMPK β regulatory subunit and phosphorylates the AMPK α catalytic subunit. This phosphorylation enhances the accessibility of the activation loop of the α subunit to phosphatases, thereby inhibiting AMPK kinase activity. Surprisingly, PI3K-Akt signaling, which is a major anabolic signaling and normally inhibits GSK3 activity, promotes GSK3 phosphorylation and inhibition of AMPK, thus revealing how AMPK senses anabolic environments in addition to cellular energy levels. Consistently, disrupting GSK3 function within the AMPK complex sustains higher AMPK activity and cellular catabolic processes even under anabolic conditions, indicating that GSK3 acts as a critical sensor for anabolic signaling to regulate AMPK.

UR - http://www.scopus.com/inward/record.url?scp=84887189624&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84887189624&partnerID=8YFLogxK

U2 - 10.1016/j.molcel.2013.03.022

DO - 10.1016/j.molcel.2013.03.022

M3 - Article

VL - 50

SP - 407

EP - 419

JO - Molecular Cell

JF - Molecular Cell

SN - 1097-2765

IS - 3

ER -