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Cited by 3,772PI3K/AKT/mTOR signaling in cancerMetabolism, Diabetes, and CancerProtein Kinase Regulation and GTPase Signaling

AKT/PKB Signaling: Navigating the Network

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Manning, Brendan D., Toker, Alex·2017·Cell
DOI 10.1016/j.cell.2017.04.001PMC PMC5546324
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Abstract

The Ser and Thr kinase AKT, also known as protein kinase B (PKB), was discovered 25 years ago and has been the focus of tens of thousands of studies in diverse fields of biology and medicine. There have been many advances in our knowledge of the upstream regulatory inputs into AKT, key multifunctional downstream signaling nodes (GSK3, FoxO, mTORC1), which greatly expand the functional repertoire of AKT, and the complex circuitry of this dynamically branching and looping signaling network that is ubiquitous to nearly every cell in our body. Mouse and human genetic studies have also revealed physiological roles for the AKT network in nearly every organ system. Our comprehension of AKT regulation and functions is particularly important given the consequences of AKT dysfunction in diverse pathological settings, including developmental and overgrowth syndromes, cancer, cardiovascular disease, insulin resistance and type 2 diabetes, inflammatory and autoimmune disorders, and neurological disorders. There has also been much progress in developing AKT-selective small molecule inhibitors. Improved understanding of the molecular wiring of the AKT signaling network continues to make an impact that cuts across most disciplines of the biomedical sciences.

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  • PI(3,4,5)P3 and its derivative PI(3,4)P2 interact with the lipid-binding PH domain in a range of protein effectors, resulting in their recruitment to membrane-signalling complexes and/or modulation of their activity.

    “PI(3,4,5)P3 and PI(3,4)P2 interact with the lipid-binding PH-domain in a range of protein effectors, resulting in their recruitment to membrane-signalling complexes and/or modulation of their activity [78–81].”

    From Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane (2020) · cites this paper as [81]

    “25 Years of AKT Signaling” states that both PIP3 and PI(3,4)P2 bind AKT’s PH domain. “PI3K-Dependent AKT Activation” and “Major Regulatory Phosphorylation Events on Akt” describe AKT’s membrane recruitment and altered activity, and the latter also describes PDK1 relocalization. The copy does not establish PH-domain binding by both lipids across the broader range of protein effectors claimed. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • AKT kinases (AKT1, AKT2, AKT3) are activated more universally downstream of receptor-mediated PI3K activation than other effectors.

    “Compared with other effectors, the AKT kinases (AKT1, AKT2, AKT3) seem to be activated more universally downstream of receptor-mediated PI3K activation (reviewed in [81,84]).”

    From Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane (2020) · cites this paper as [81]

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Authors
Manning, B. D., & Toker, A.
Affiliations
  • Harvard University (US)
  • Beth Israel Deaconess Medical Center (US)
Corresponding author
  • Manning, Brendan D.
  • Toker, Alex
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2017-04
Volume
169
Issue
3
Pages
381-405
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2017.04.001
PMC
PMC5546324
OpenAlex
W2606513998
Cited by
3,772
References
15
Citations by year
2026: 486 · 2025: 434 · 2024: 440 · 2023: 354 · 2022: 453 · 2021: 487 · 2020: 484 · 2019: 343 · 2018: 240 · 2017: 48
FWCI
28.87
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (R35-CA197459, P01-CA120964, R01-CA200671, R01-CA177910)
  • Ludwig Center at Harvard
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 › Metabolism, Diabetes, and Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
Akt, glycogen synthase kinase-3, FOXO, mTORC1, cancer, insulin resistance, type 2 diabetes, overgrowth syndromes, cardiovascular disease, autoimmune disease, neurological disorders
MeSH terms
Animals, Drug Therapy, Humans, Isoenzymes, Phosphorylation, Signal Transduction, Proto-Oncogene Proteins c-akt, Molecular Targeted Therapy

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