Regulation of Akt/PKB activation by tyrosine phosphorylation

Citation
Ry. Chen et al., Regulation of Akt/PKB activation by tyrosine phosphorylation, J BIOL CHEM, 276(34), 2001, pp. 31858-31862
Citations number
25
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN journal
0021-9258 → ACNP
Volume
276
Issue
34
Year of publication
2001
Pages
31858 - 31862
Database
ISI
SICI code
0021-9258(20010824)276:34<31858:ROAABT>2.0.ZU;2-F
Abstract
Activation of Akt/PHB by growth factors requires multiple phosphorylation e vents. Phosphorylation of Thr(308) and Ser(473) of Akt by its upstream kina se(s) or autophosphorylation is critical for optimal activation of its kina se activity. Here, we present evidence that tyrosine phosphorylation is req uired for Akt activation. Epidermal growth factor treatment induces tyrosin e phosphorylation of Akt in COS1 and PC3M cells, which is abrogated by PP2, a selective inhibitor for Src family tyrosine kinases. Elevated Akt activi ty is observed in v-Src transformed NIH3T3 cells, which is accompanied with increased tyrosine phosphorylation of Akt. Akt activity induced by growth factors is significantly reduced in SYF cells lacking Src, Yes, and Fyn, wh ich can be restored by introducing c-Src, but not the kinase-inactive Src, back to these cells. Furthermore, we have identified two tyrosine residues near the activation loop of Akt that are important for its activation. Subs titution of these residues with phenylalanine abolishes Akt kinase activity stimulated by growth factors. These two YF mutants fail to block Forkhead transcription factor activity in 293 cells and are unable to prevent apopto sis induced by matrix detachment. Our data suggest that, in addition to pho sphorylation of Thr(308) and Ser(473), tyrosine phosphorylation of Akt may be essential for its biological function.