The pro‐apoptotic kinase Mst1 and its caspase cleavage products are direct inhibitors of Akt1
Open accessAbstract
Akt kinases mediate cell growth and survival. Here, we report that a pro-apoptotic kinase, Mst1/STK4, is a physiological Akt1 interaction partner. Mst1 was identified as a component of an Akt1 multiprotein complex isolated from lipid raft-enriched fractions of LNCaP human prostate cancer cells. Endogenous Mst1, along with its paralog, Mst2, acted as inhibitors of endogenous Akt1. Surprisingly, mature Mst1 as well as both of its caspase cleavage products, which localize to distinct subcellular compartments and are not structurally homologous, complexed with and inhibited Akt1. cRNAs encoding full-length Mst1, and N- and C-terminal caspase Mst1 cleavage products, reverted an early lethal phenotype in zebrafish development induced by expression of membrane-targeted Akt1. Mst1 and Akt1 localized to identical subcellular sites in human prostate tumors. Mst1 levels declined with progression from clinically localized to hormone refractory disease, coinciding with an increase in Akt activation with transition from hormone naïve to hormone-resistant metastases. These results position Mst1/2 within a novel branch of the phosphoinositide 3-kinase/Akt pathway and suggest an important role in cancer progression.
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Mst1 binds and inhibits Akt1.
“In another study, the Hippo kinase Mst1 (gene symbol Stk4 ) was shown to bind and inhibit Akt1 (also known as Pkb) (22).”
From The Hippo signal transduction network for exercise physiologists (2016) · cites this paper as [22]
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References 51 · Cited by 136
- Authors
- Cinar, B., Fang, P., Lutchman, M., Di Vizio, D., Adam, R. M., Pavlova, N., Rubin, M. A., Yelick, P. C., & Freeman, M. R.
- Affiliations
- Boston Children's Hospital (US)
- Harvard University (US)
- Brigham and Women's Hospital (US)
- Tufts University (US)
- Corresponding author
- Freeman, Michael R
- Venue
- The EMBO Journal
- Published
- 2007-10-11
- Volume
- 26
- Issue
- 21
- Pages
- 4523-4534
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC2063482
- OpenAlex
- W2106401943
- Cited by
- 136
- References
- 51
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 6 · 2023: 4 · 2022: 7 · 2021: 5 · 2020: 7 · 2019: 8 · 2018: 5 · 2017: 7 · 2016: 9 · 2015: 7 · 2014: 9 · 2013: 10 · 2012: 8
- FWCI
- 3.18
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Defense (W81XWH)
- American Urological Association Foundation
- American-Italian Cancer Foundation
- National Institutes of Health (5r01ca112303-05, W81XWH, CA112303)
- National Cancer Institute (R01-CA-112303)
- National Institute of Diabetes and Digestive and Kidney Diseases (R37 DK47556, P50DK65298, R37DK047556, P50DK065298)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Keywords
- MST1, MST2, AKT1, kinase inhibition, phosphoinositide 3-kinase/Akt pathway, prostate cancer, castration-resistant prostate cancer, apoptosis, lipid rafts, tumor progression, protein-protein interaction
- MeSH terms
- Hippo Kinases, Animals, Humans, Male, Models, Biological, Phenotype, Zebrafish, Gene Expression Regulation, Neoplastic, Apoptosis, Protein Serine-Threonine Kinases, Protein Structure, Tertiary, Disease Progression, Caspases, Membrane Microdomains, Cell Line, Tumor, Intracellular Signaling Peptides and Proteins, Proto-Oncogene Proteins c-akt
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