An ATP-site on-off switch that restricts phosphatase accessibility of Akt.
Sci Signal
; 5(223): ra37, 2012 May 08.
Article
em En
| MEDLINE
| ID: mdl-22569334
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Trifosfato de Adenosina
/
Monoéster Fosfórico Hidrolases
/
Proteínas Proto-Oncogênicas c-akt
Idioma:
En
Revista:
Sci Signal
Assunto da revista:
CIENCIA
/
FISIOLOGIA
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Estados Unidos