LKB1 tumor suppressor regulates AMP kinase/mTOR-independent cell growth and proliferation via the phosphorylation of Yap
Open accessAbstract
The liver kinase B1 (LKB1) tumor suppressor inhibits cell growth through its regulation of cellular metabolism and apical-basal polarity. The best understood mechanism whereby LKB1 limits cell growth is through activation of the AMP-activated-protein-kinase/mammalian-target-of-rapamycin (AMPK/mTOR) pathway to control metabolism. As LKB1 is also required for polarized epithelial cells to resist hyperplasia, it is anticipated to function through additional mechanisms. Recently, Yes-associated protein (Yap) has emerged as a transcriptional co-activator that modulates tissue homeostasis in response to cell-cell contact. Thus this study examined a possible connection between Yap and LKB1. Restoration of LKB1 expression in HeLa cells, which lack this tumor suppressor, or short-hairpin RNA knockdown of LKB1 in NTERT immortalized keratinocytes, demonstrated that LKB1 promotes Yap phosphorylation, nuclear exclusion and proteasomal degradation. The ability of phosphorylation-defective Yap mutants to rescue LKB1 phenotypes, such as reduced cell proliferation and cell size, suggest that Yap inhibition contributes to LKB1 tumor suppressor function(s). However, failure of Lats1/2 knockdown to suppress LKB1-mediated Yap regulation suggested that LKB1 signals to Yap via a non-canonical pathway. Additionally, LKB1 inhibited Yap independently of either AMPK or mTOR activation. These findings reveal a novel mechanism whereby LKB1 may restrict cancer cell growth via the inhibition of Yap.
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LKB1 is an AMPK-independent YAP regulator.
“Finally, two studies have identified the AMPK-kinase LKB1 (gene symbol STK11 ) as an AMPK-independent YAP regulator (101, 108).”
From The Hippo signal transduction network for exercise physiologists (2016) · cites this paper as [108]
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Mechanisms and Molecular Biology of Major Tumor Suppressors
Engel, B. E. (2014) · Digital Commons - University of South Florida (University of South Florida)
- Authors
- Nguyen, H. B., Babcock, J. T., Wells, C. D., & Quilliam, L. A.
- Affiliations
- Indiana University Indianapolis (US)
- Indiana University School of Medicine (US)
- Corresponding author
- Quilliam, L A
- Venue
- Oncogene
- Published
- 2012-10-01
- Volume
- 32
- Issue
- 35
- Pages
- 4100-4109
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- PMC
- PMC3977597
- OpenAlex
- W1996122722
- Cited by
- 84
- References
- 46
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 1 · 2023: 4 · 2022: 2 · 2021: 5 · 2020: 8 · 2019: 5 · 2018: 5 · 2017: 11 · 2016: 8 · 2015: 14 · 2014: 10 · 2013: 2 · 2012: 1
- FWCI
- 4.09
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- Funders
- U.S. Department of Defense
- LAM Foundation
- Indiana University-Purdue University Indianapolis
- National Cancer Institute (R01CA151765)
- 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 › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- LKB1, tumor suppressor, YAP, YAP phosphorylation, nuclear exclusion, proteasomal degradation, cell proliferation, cell growth, cell size, LATS1/2, AMPK/mTOR signaling, apical-basal polarity, epithelial hyperplasia, keratinocytes, HeLa cells
- MeSH terms
- YAP-Signaling Proteins, AMP-Activated Protein Kinase Kinases, Adenylate Kinase, HeLa Cells, Humans, Phosphoproteins, Phosphorylation, Transcription Factors, Transcription, Genetic, Protein Serine-Threonine Kinases, Stress Fibers, Tumor Suppressor Proteins, Proteasome Endopeptidase Complex, Cell Size, Adaptor Proteins, Signal Transducing, Cell Proliferation, TOR Serine-Threonine Kinases
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