AMPK modulates Hippo pathway activity to regulate energy homeostasis
Open accessAbstract
The Hippo pathway was discovered as a conserved tumour suppressor pathway restricting cell proliferation and apoptosis. However, the upstream signals that regulate the Hippo pathway in the context of organ size control and cancer prevention are largely unknown. Here, we report that glucose, the ubiquitous energy source used for ATP generation, regulates the Hippo pathway downstream effector YAP. We show that both the Hippo pathway and AMP-activated protein kinase (AMPK) were activated during glucose starvation, resulting in phosphorylation of YAP and contributing to its inactivation. We also identified glucose-transporter 3 (GLUT3) as a YAP-regulated gene involved in glucose metabolism. Together, these results demonstrate that glucose-mediated energy homeostasis is an upstream event involved in regulation of the Hippo pathway and, potentially, an oncogenic function of YAP in promoting glycolysis, thereby providing an exciting link between glucose metabolism and the Hippo pathway in tissue maintenance and cancer prevention.
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Direct phosphorylation of YAP on Ser61/94 is key for the interaction between Yap and Teads.
“and the direct phosphorylation of YAP on Ser61/94, which is key for the interaction between Yap and Teads (100, 145).”
From The Hippo signal transduction network for exercise physiologists (2016) · cites this paper as [145]
The Results section (page not provided) identifies S61 and S94 as AMPK phosphorylation sites and reports that an S94 phospho-mimetic greatly diminished YAP–TEAD interaction. It also reports that an S61 phospho-mimetic did not noticeably affect that interaction, so the claim is not supported for S61. (LLM, conf=0.90)
Experimental — accuracy not yet measuredGlucose and AMPK are endurance-exercise-related signals that have been linked to YAP/TAZ.
“Endurance exercise-associated signals linked to YAP/TAZ”
From The Hippo signal transduction network for exercise physiologists (2016) · cites this paper as Wang et al Nature Cell Biol (2015)
The Results sections on glucose homeostasis and AMPK show that glucose availability affects YAP phosphorylation and that AMPK associates with and phosphorylates YAP (pages not provided). The paper therefore supports a link between both signals and YAP, but our copy does not establish that they are endurance-exercise-associated signals or show a corresponding link to TAZ. (LLM, conf=0.86)
Experimental — accuracy not yet measuredBoth glucose starvation and AMPK activators inhibit Yap in different cell types.
“Both glucose starvation (36, 100, 145) and AMPK activators (26, 100, 145) inhibit Yap in different cell types.”
From The Hippo signal transduction network for exercise physiologists (2016) · cites this paper as [145]
Experimental — accuracy not yet measuredHippo signalling responds to glucose and regulates the expression of glucose transporters.
“Also, because Hippo signalling responds to glucose and regulates the expression of glucose transporters (145)”
From The Hippo signal transduction network for exercise physiologists (2016) · cites this paper as [145]
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- Authors
- Wang, W., Xiao, Z.-D., Li, X., Aziz, K. E., Gan, B., Johnson, R. L., & Chen, J.
- Affiliations
- The University of Texas System (US)
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Chen, Junjie
- Venue
- Nature Cell Biology
- Published
- 2015-03-09
- Volume
- 17
- Issue
- 4
- Pages
- 490-499
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC4380807
- OpenAlex
- W2020511240
- Cited by
- 549
- References
- 40
- Citations by year
- 2026: 31 · 2025: 51 · 2024: 57 · 2023: 40 · 2022: 53 · 2021: 55 · 2020: 72 · 2019: 43 · 2018: 52 · 2017: 41 · 2016: 33 · 2015: 19
- FWCI
- 25.72
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Cancer Institute (CA 016672, R01CA089239, R01CA092312, R01CA181196, P30CA016672)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK102611)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- AMPK, Hippo signaling pathway, YAP, energy homeostasis, glucose metabolism, glucose deprivation, GLUT3, YAP phosphorylation, organ size control, tumor suppression, glycolysis, cancer prevention
- MeSH terms
- Hippo Signaling Pathway, YAP-Signaling Proteins, Animals, Colonic Neoplasms, Energy Metabolism, Enzyme Activation, Female, Glucose, Glycolysis, HeLa Cells, Humans, Liver Neoplasms, Mice, Inbred C57BL, Phosphoproteins, Phosphorylation, Starvation, Transcription, Genetic, Protein Serine-Threonine Kinases, Cell Cycle Proteins, rho GTP-Binding Proteins, Cell Line, Tumor, Adaptor Proteins, Signal Transducing, Glucose Transporter Type 3, Mice, AMP-Activated Protein Kinases, HEK293 Cells
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