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Sci. Signal., 8 May 2012
Vol. 5, Issue 223, p. ra37
[DOI: 10.1126/scisignal.2002618]
RESEARCH ARTICLES
Editor's Summary
Protecting Active Akt
The kinase Akt is activated by phosphorylation of two specific residues; dephosphorylation of these residues by phosphatases results in inactivation. Thus, the phosphorylation status of these residues is often used as an indicator of Akt kinase activity. ATP-competitive inhibitors attenuate the activity of Akt by preventing the binding of ATP to the kinase; however, the kinase remains phosphorylated. Using biochemical and cellular assays and structural analysis, Lin et al. explain this paradox: ATP-competitive inhibitors, as well as ATP, stabilized a conformation in which the activating phosphorylated residues were inaccessible to phosphatases, whereas ADP enabled dephosphorylation and inactivation of Akt. In addition, ATP-competitive inhibitors preferentially targeted active Akt. Because the activity of Akt is frequently increased in cancer cells, these results suggest that it might be possible to selectively target Akt in cancer cells while sparing normal cells with lower Akt activity.
Citation: K. Lin, J. Lin, W.-I. Wu, J. Ballard, B. B. Lee, S. L. Gloor, G. P. A. Vigers, T. H. Morales, L. S. Friedman, N. Skelton, B. J. Brandhuber, An ATP-Site On-Off Switch That Restricts Phosphatase Accessibility of Akt. Sci. Signal.5, ra37 (2012).
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