Targeting negative phosphorylation to activate AMPK
AMPK is a master regulator of metabolism and is highly conserved and ubiquitously expressed. Activation of AMPK stimulates the catabolic pathway (glucose utilization and β-oxidation) and inhibits the anabolic pathway (gluconeogenesis, protein synthesis, and lipogenesis), leading to improvement of ce...
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| Format: | Article |
| Language: | English |
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Bioscientifica
2025-07-01
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| Series: | Endocrine Connections |
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| Online Access: | https://ec.bioscientifica.com/view/journals/ec/14/7/EC-25-0260.xml |
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| _version_ | 1849429652373766144 |
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| author | Alexia Pearah Balamurugan Ramatchandirin Karina Ramirez Sally Radovick Fredric E Wondisford Ling He |
| author_facet | Alexia Pearah Balamurugan Ramatchandirin Karina Ramirez Sally Radovick Fredric E Wondisford Ling He |
| author_sort | Alexia Pearah |
| collection | DOAJ |
| description | AMPK is a master regulator of metabolism and is highly conserved and ubiquitously expressed. Activation of AMPK stimulates the catabolic pathway (glucose utilization and β-oxidation) and inhibits the anabolic pathway (gluconeogenesis, protein synthesis, and lipogenesis), leading to improvement of cellular energy status. However, the mechanisms of maintaining low cellular AMPK activity are not fully understood. We and other investigators showed that activated PKA in the glucagon-cAMP signaling pathway and insulin-activated AKT both can directly phosphorylate AMPKα1/2 at S496/491 to inhibit AMPK activity. In the current study, we found that activation of AMPK by an activator, AICAR, led to elevated and prolonged phosphorylation of AMPKα1/2 at S496/S491, reflecting a feedback inhibition of AMPK activity. In an in vitro assay, functional AMPKα1β1γ1 or AMPKα2β1γ1 can phosphorylate AMPKα1 at S496 or AMPKα2 at S491, respectively. We designed and successfully screened a new AMPKα2-targeting peptide to activate AMPK through competitively blocking the negative phosphorylation, resulting in suppression of gluconeogenic gene expression and promotion of mitochondrial fission in hepatocytes. |
| format | Article |
| id | doaj-art-3b1d6b2570a34d0d8e4e4544df77156f |
| institution | Kabale University |
| issn | 2049-3614 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Bioscientifica |
| record_format | Article |
| series | Endocrine Connections |
| spelling | doaj-art-3b1d6b2570a34d0d8e4e4544df77156f2025-08-20T03:28:18ZengBioscientificaEndocrine Connections2049-36142025-07-0114710.1530/EC-25-02601Targeting negative phosphorylation to activate AMPKAlexia Pearah0Balamurugan Ramatchandirin1Karina Ramirez2Sally Radovick3Fredric E Wondisford4Ling He5Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USADepartment of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USADepartment of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, Arizona, USADepartment of Medicine, University of Arizona College of Medicine, Phoenix, Arizona, USADepartment of Medicine, University of Arizona College of Medicine, Phoenix, Arizona, USADepartment of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USAAMPK is a master regulator of metabolism and is highly conserved and ubiquitously expressed. Activation of AMPK stimulates the catabolic pathway (glucose utilization and β-oxidation) and inhibits the anabolic pathway (gluconeogenesis, protein synthesis, and lipogenesis), leading to improvement of cellular energy status. However, the mechanisms of maintaining low cellular AMPK activity are not fully understood. We and other investigators showed that activated PKA in the glucagon-cAMP signaling pathway and insulin-activated AKT both can directly phosphorylate AMPKα1/2 at S496/491 to inhibit AMPK activity. In the current study, we found that activation of AMPK by an activator, AICAR, led to elevated and prolonged phosphorylation of AMPKα1/2 at S496/S491, reflecting a feedback inhibition of AMPK activity. In an in vitro assay, functional AMPKα1β1γ1 or AMPKα2β1γ1 can phosphorylate AMPKα1 at S496 or AMPKα2 at S491, respectively. We designed and successfully screened a new AMPKα2-targeting peptide to activate AMPK through competitively blocking the negative phosphorylation, resulting in suppression of gluconeogenic gene expression and promotion of mitochondrial fission in hepatocytes.https://ec.bioscientifica.com/view/journals/ec/14/7/EC-25-0260.xmlampk phosphorylationtargeting-peptidegluconeogenic gene expression |
| spellingShingle | Alexia Pearah Balamurugan Ramatchandirin Karina Ramirez Sally Radovick Fredric E Wondisford Ling He Targeting negative phosphorylation to activate AMPK Endocrine Connections ampk phosphorylation targeting-peptide gluconeogenic gene expression |
| title | Targeting negative phosphorylation to activate AMPK |
| title_full | Targeting negative phosphorylation to activate AMPK |
| title_fullStr | Targeting negative phosphorylation to activate AMPK |
| title_full_unstemmed | Targeting negative phosphorylation to activate AMPK |
| title_short | Targeting negative phosphorylation to activate AMPK |
| title_sort | targeting negative phosphorylation to activate ampk |
| topic | ampk phosphorylation targeting-peptide gluconeogenic gene expression |
| url | https://ec.bioscientifica.com/view/journals/ec/14/7/EC-25-0260.xml |
| work_keys_str_mv | AT alexiapearah targetingnegativephosphorylationtoactivateampk AT balamuruganramatchandirin targetingnegativephosphorylationtoactivateampk AT karinaramirez targetingnegativephosphorylationtoactivateampk AT sallyradovick targetingnegativephosphorylationtoactivateampk AT fredricewondisford targetingnegativephosphorylationtoactivateampk AT linghe targetingnegativephosphorylationtoactivateampk |