Article abstract
Nature Chemical Biology 5, 484 - 493 (2009)
Published online: 24 May 2009 | doi:10.1038/nchembio.183
Inhibitor hijacking of Akt activation
Tatsuya Okuzumi1, Dorothea Fiedler1, Chao Zhang1, Daniel C Gray2, Brian Aizenstein3, Randy Hoffman3 & Kevan M Shokat1,4
Abstract
The kinase Akt plays a central role as a regulator of multiple growth factor input signals, thus making it an attractive anticancer 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 explored 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 revealed 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. These results provide new insights into both natural regulation of Akt activation and Akt inhibitors entering the clinic.
- Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, California, USA.
- Chemistry and Chemical Biology Graduate Program, University of California, San Francisco, San Francisco, California, USA.
- SelectScreen Services, Discovery Assays and Services, Cell Systems Division, Invitrogen Corporation, Madison, Wisconsin, USA.
- Department of Chemistry, University of California, Berkeley, Berkeley, California, USA.
Correspondence to: Kevan M Shokat1,4 e-mail: shokat@cmp.ucsf.edu
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