The DOI matches its Crossref record; 5 of the 5 references it cites were found in a registry or an index.
Inhibitor hijacking of Akt activation
Open accessAbstract
The kinase Akt plays a central role as a regulator of multiple growth factor input signals, making it an attractive anti-cancer drug target. A-443654 is an ATP-competitive Akt inhibitor. Unexpectedly, treatment of cells with A-443654 causes paradoxical hyperphosphorylation of Akt at its two regulatory sites (Thr308 and Ser473). We explore whether inhibitor-induced hyperphosphorylation of Akt by A-443654 is a consequence of disrupted feedback regulation at a pathway level or whether it is a direct consequence of inhibitor binding to the ATP binding site of Akt. Catalytically inactive mutants of Akt reveal that binding of an inhibitor to the ATP site of Akt is sufficient to directly cause hyperphosphorylation of the kinase in the absence of any pathway feedback effects. We conclude that ATP-competitive Akt inhibitors impart regulatory phosphorylation of their target kinase Akt providing new insights into both natural regulation of Akt activation and Akt inhibitors entering the clinic.
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Cites
Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex
Sarbassov, D. D., Guertin, D. A., Ali, S. M., & Sabatini, D. M. (2005) · Science · doi:10.1126/science.1106148 · Cited by 6,216
The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism
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Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity
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Self-citationMitogenic Activation, Phosphorylation, and Nuclear Translocation of Protein Kinase Bβ
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Manning, B. D., & Toker, A. (2017) · Cell · doi:10.1016/j.cell.2017.04.001 · Cited by 3,772
The translational landscape of mTOR signalling steers cancer initiation and metastasis
Hsieh, A. C., Liu, Y., Edlind, M. P., Ingolia, N. T., Janes, M. R., Sher, A., Shi, E. Y., Stumpf, C. R., Christensen, C., Bonham, M. J., et al. (2012) · Nature · doi:10.1038/nature10912 · Cited by 1,313
Self-citationThe nuts and bolts of AGC protein kinases
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AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity
Chandarlapaty, S., Sawai, A., Scaltriti, M., Rodrik-Outmezguine, V., Grbovic-Huezo, O., Serra, V., Majumder, P. K., Baselga, J., & Rosen, N. (2011) · Cancer Cell · doi:10.1016/j.ccr.2010.10.031 · Cited by 967
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Metadata
- Authors
- Okuzumi, T., Fiedler, D., Zhang, C., Gray, D. C., Aizenstein, B., Hoffman, R., & Shokat, K. M.
- Venue
- Nature Chemical Biology
- Published
- 2009-05-24
- Volume
- 5
- Issue
- 7
- Pages
- 484-493
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- OpenAlex
- W2134831715
- Cited by
- 294
- References
- 5
- FWCI
- 10.80
- Type
- journal article
- Language
- en
- Open access
- green
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- Okuzumi, T., Fiedler, D., Zhang, C., Gray, D. C., Aizenstein, B., Hoffman, R., & Shokat, K. M. (2009). Inhibitor hijacking of Akt activation. Nature Chemical Biology. https://doi.org/10.1038/nchembio.183
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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