ArticleThe Journal of biological chemistry2015
Alternative Activation Mechanisms of Protein Kinase B Trigger Distinct Downstream Signaling Responses.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
What it found
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Who cites it
12 citing papers in PubMed, 15 citations in OpenAlex.
- Structural and mechanistic basis of mTORC2 activation of protein kinase AKT/PKB.The Biochemical journal · 2026Review
- Food for thought: Nutrient metabolism controlling early T cell development.BioEssays : news and reviews in molecular, cellular and developmental biology · 2025Review
- The mTORC2 signaling network: targets and cross-talks.The Biochemical journal · 2024Review
- Structure of autoinhibited Akt1 reveals mechanism of PIPProceedings of the National Academy of Sciences of the United States of America · 2021Article
- Control of Akt activity and substrate phosphorylation in cells.IUBMB life · 2020Review
- Serine 474 phosphorylation is essential for maximal Akt2 kinase activity in adipocytes.The Journal of biological chemistry · 2019Article
- Lipid-dependent Akt-ivity: where, when, and how.Biochemical Society transactions · 2019Review
- Getting the Akt Together: Guiding Intracellular Akt Activity by PI3K.Biomolecules · 2019Review
- The antipsychotic agent flupentixol is a new PI3K inhibitor and potential anticancer drug for lung cancer.International journal of biological sciences · 2019Article
- Conformational sampling of membranes by Akt controls its activation and inactivation.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Review
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Corrections and comments
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Authors and funding
9 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Protein kinase B (PKB/Akt) is an important mediator of signals that control various cellular processes including cell survival, growth, proliferation, and metabolism. PKB promotes these processes by phosphorylating many cellular targets, which trigger distinct downstream signaling events. However, how PKB is able to selectively target its substrates to induce specific cellular functions remains elusive. Here we perform a systematic study to dissect mechanisms that regulate intrinsic kinase activity versus mechanisms that specifically regulate activity toward specific substrates. We demonstrate that activation loop phosphorylation and the C-terminal hydrophobic motif are essential for high PKB activity in general. On the other hand, we identify membrane targeting, which for decades has been regarded as an essential step in PKB activation, as a mechanism mainly affecting substrate selectivity. Further, we show that PKB activity in cells can be triggered independently of PI3K by initial hydrophobic motif phosphorylation, presumably through a mechanism analogous to other AGC kinases. Importantly, different modes of PKB activation result in phosphorylation of distinct downstream targets. Our data indicate that specific mechanisms have evolved for signaling nodes, like PKB, to select between various downstream events. Targeting such mechanisms selectively could facilitate the development of therapeutics that might limit toxic side effects.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.