REGULATION OF CELL-DEATH PROTEASE CASPASE-9 BY PHOSPHORYLATION

Caspases are intracellular proteases that function as initiators and e ffectors of apoptosis. The kinase Akt and p21-Ras, an Akt activator, i nduced phosphorylation of pro-caspase-9 (pro-Casp9) in cells. Cytochro me c-induced proteolytic processing of pro-Casp9 was defective in cyto solic extracts from cells expressing either active Ras or Akt. Akt pho sphorylated recombinant Casp9 in vitro on serine-196 and inhibited its protease activity. Mutant pro-Casp9(Ser196Ala) was resistant to Akt-m ediated phosphorylation and inhibition in vitro and in cells, resultin g in Akt-resistant induction of apoptosis. Thus, caspases can be direc tly regulated by protein phosphorylation.