Cleavage and inactivation of antiapoptotic Akt/PKB by caspases during apoptosis.
The oncogene Akt/PKB/RAC-PK is a serine/threonine kinase that mediates survival signals and has protective effects against apoptosis induced by a variety of stimuli. The kinase activity of Akt has been demonstrated to be critical in transmitting survival signals. We found that Akt protein was down-regulated during apoptosis. The down-regulation was blocked by a caspase inhibitor, indicating that Akt was cleaved by caspases during apoptosis. The Akt protein incubation with active caspases in vitro revealed that it was cleaved at three sites to produce 40- and 44-kDa fragments. The two cleavage sites were between the NH(2)-terminal pleckstrin homology domain (PH domain) and the kinase domain (TVAD(108 downward arrow)G and EEMD(119 downward arrow)F) and in the COOH-terminal regulatory domain (SETD(434 downward arrow)T). The loss of COOH-terminal domain of the Akt protein reduced its kinase activity and the overexpression of NH(2)-terminal and COOH-terminal-deleted Akt fragment increased the sensitivity to apoptosis-inducing stimuli. These results indicate that caspase-dependent cleavage of anti-apoptotic Akt turns off the survival signals, resulting in the acceleration of apoptotic cell death.
Rokudai
S
S
Institute of Molecular and Cellular Biosciences, University of Tokyo, Japan.
Fujita
N
N
Hashimoto
Y
Y
Tsuruo
T
T
D017209:Apoptosis / Q000502:physiology*; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D015536:Down-Regulation; D006801:Humans; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D010770:Phosphotransferases / Q000032:analysis / Q000037:antagonists & inhibitors; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt
D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D010770:Phosphotransferases; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases