Regulation of Akt/PKB Activation by Tyrosine Phosphorylation

Activation of Akt/PKB by growth factors requires multiple phosphorylation events. Phosphorylation of Thr 308 and Ser 473 of Akt by its upstream kinase(s) or autophosphorylation is critical for optimal activation of its kinase activity. Here, we present evidence that tyrosine phosphorylation is requi...

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Bibliographic Details
Published in:The Journal of biological chemistry 2001-08, Vol.276 (34), p.31858-31862
Main Authors: Chen, R, Kim, O, Yang, J, Sato, K, Eisenmann, K M, McCarthy, J, Chen, H, Qiu, Y
Format: Article
Language:English
Subjects:
Akt protein
Amino Acid Sequence
Animals
Cell Line
Enzyme Activation
Humans
Mice
Molecular Sequence Data
Oncogene Protein pp60(v-src) - metabolism
Phosphorylation
protein kinase B
Protein-Serine-Threonine Kinases
Proto-Oncogene Proteins - metabolism
Proto-Oncogene Proteins c-akt
tyrosine
Tyrosine - metabolism
v-src gene
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Summary:Activation of Akt/PKB by growth factors requires multiple phosphorylation events. Phosphorylation of Thr 308 and Ser 473 of Akt by its upstream kinase(s) or autophosphorylation is critical for optimal activation of its kinase activity. Here, we present evidence that tyrosine phosphorylation is required for Akt activation. Epidermal growth factor treatment induces tyrosine phosphorylation of Akt in COS1 and PC3M cells, which is abrogated by PP2, a selective inhibitor for Src family tyrosine kinases. Elevated Akt activity 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, which 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. Substitution 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 apoptosis induced by matrix detachment. Our data suggest that, in addition to phosphorylation of Thr 308 and Ser 473 , tyrosine phosphorylation of Akt may be essential for its biological function.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.C100271200