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Sci. Signal., 8 May 2012
Vol. 5, Issue 223, p. ra37
[DOI: 10.1126/scisignal.2002618]


An ATP-Site On-Off Switch That Restricts Phosphatase Accessibility of Akt

Kui Lin1*, Jie Lin1, Wen-I Wu2, Joshua Ballard2, Brian B. Lee1, Susan L. Gloor2{dagger}, Guy P. A. Vigers2, Tony H. Morales2, Lori S. Friedman1, Nicholas Skelton1, and Barbara J. Brandhuber2*

1 Genentech Inc., South San Francisco, CA 94080, USA.
2 Array BioPharma Inc., Boulder, CO 80301, USA.

{dagger} Present address: Luca Technologies Inc., Golden, CO 80401, USA.

Abstract: The protein serine-threonine kinase Akt undergoes a substantial conformational change upon activation, which is induced by the phosphorylation of two critical regulatory residues, threonine 308 and serine 473. Paradoxically, treating cells with adenosine 5'-triphosphate (ATP)–competitive inhibitors of Akt results in increased phosphorylation of both residues. We show that binding of ATP-competitive inhibitors stabilized a conformation in which both phosphorylated sites were inaccessible to phosphatases. ATP binding also produced this protection of the phosphorylated sites, whereas interaction with its hydrolysis product adenosine 5'-diphosphate (ADP) or allosteric Akt inhibitors resulted in increased accessibility of these phosphorylated residues. ATP-competitive inhibitors mimicked ATP by targeting active Akt. Forms of Akt activated by an oncogenic mutation or myristoylation were more potently inhibited by the ATP-competitive inhibitors than was wild-type Akt. These data support a new model of kinase regulation, wherein nucleotides modulate an on-off switch in Akt through conformational changes, which is disrupted by ATP-competitive inhibitors.

* To whom correspondence should be addressed. E-mail: klin{at} (K.L.); bbrandhuber{at} (B.J.B.)

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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