Akt-Mediated Regulation of Autophagy and Tumorigenesis Through Beclin 1 Phosphorylation
Open accessAbstract
Getting Autophagy to Akt: The protein kinase Akt is often activated in human cancers and is thought to promote tumor formation. One way in which it may do so is to inhibit autophagy (a process by which the cell digests its own proteins or organelles, especially damaged ones). Wang et al. (p. 956 , published online 25 October; see the Perspective by Koren and Kimchi ) provide a direct molecular mechanism by which Akt regulates autophagy. Beclin, a component of the autophagy machinery, appears to be a direct target of phosphorylation by Akt. Such phosphorylation enhanced interaction of Beclin with intermediate filaments of the cyto skeleton and inhibited autophagy. Expression of a modified Beclin 1 molecule that could not be phosphorylated by Akt inhibited Akt-induced transformation of cells in culture and tumor formation in a mouse model.
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MTOR-independent methods for stimulating autophagy include direct stimulation of AKT and BECN1, activating MAPK8/JNK1 to dissociate BCL2 from BECN1, applying Tat-Beclin 1, SIRT1-associated starvation, and disrupting nonsense-mediated RNA decay.
“The array of MTOR-independent methods for stimulating autophagy also includes direct stimulation of AKT and BECN1, activating MAPK8/JNK1 to dissociate BCL2 from (and thereby disinhibit) BECN1, applying the synthetic peptide Tat-Beclin 1, SIRT1-associated starvation, and disrupting nonsense-mediated RNA decay [513–517] (Figure 3).”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [514]
MTOR activation is an indicator of suppressed autophagy, as is p-BECN1 at Ser234 where it is targeted by AKT1 during MTOR activation.
“MTOR activation is an indicator of suppressed autophagy 31 as is p-BECN1 at this Ser234 residue where it is targeted by the serine/threonine kinase AKT1 during MTOR activation.32”
From RUBCN/rubicon and EGFR regulate lysosomal degradative processes in the retinal pigment epithelium (RPE) of the eye (2017) · cites this paper as [32]
Hallmarks of suppressed autophagy indicate that LAP and autophagy may be competing for resources and might not easily co-exist in RPE cells.
“These hallmarks of suppressed autophagy 11,31,32 indicate that LAP and autophagy may be competing for resources and might not easily co-exist in RPE cells.”
From RUBCN/rubicon and EGFR regulate lysosomal degradative processes in the retinal pigment epithelium (RPE) of the eye (2017) · cites this paper as [32]
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References 24 · Cited by 728
- Authors
- Wang, R. C., Wei, Y., An, Z., Zou, Z., Xiao, G., Bhagat, G., White, M., Reichelt, J., & Levine, B.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Howard Hughes Medical Institute (US)
- NewYork–Presbyterian Hospital (US)
- Newcastle University (GB)
- Corresponding author
- Levine, Beth
- ORCID
- Venue
- Science
- Published
- 2012-11-16
- Volume
- 338
- Issue
- 6109
- Pages
- 956-959
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC3507442
- OpenAlex
- W2077418979
- Cited by
- 728
- References
- 24
- Citations by year
- 2026: 20 · 2025: 32 · 2024: 30 · 2023: 50 · 2022: 54 · 2021: 55 · 2020: 61 · 2019: 53 · 2018: 70 · 2017: 51 · 2016: 59 · 2015: 71 · 2014: 60 · 2013: 58 · 2012: 4
- FWCI
- 46.46
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- Howard Hughes Medical Institute
- National Cancer Institute (R01 CA84254-S1, R01CA129451, K08CA164047, R01CA071443, R01CA109618, R01CA084254, P30CA142543)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- Beclin-1, Akt phosphorylation, autophagy, carcinogenesis, PI3K/Akt signaling, 14-3-3 proteins, vimentin intermediate filaments, anchorage-independent growth, tumor suppressor
- MeSH terms
- Beclin-1, Animals, Autophagy, Cell Transformation, Neoplastic, Fibroblasts, HeLa Cells, Humans, Membrane Proteins, Phosphorylation, Transduction, Genetic, Vimentin, Xenograft Model Antitumor Assays, RNA, Small Interfering, Cell Line, Tumor, Apoptosis Regulatory Proteins, Proto-Oncogene Proteins c-akt, Mice, Rats
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