Regulation of Cell Death Protease Caspase-9 by Phosphorylation

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Science  13 Nov 1998:
Vol. 282, Issue 5392, pp. 1318-1321
DOI: 10.1126/science.282.5392.1318

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Caspases are intracellular proteases that function as initiators and effectors of apoptosis. The kinase Akt and p21-Ras, an Akt activator, induced phosphorylation of pro–caspase-9 (pro-Casp9) in cells. Cytochrome c–induced proteolytic processing of pro-Casp9 was defective in cytosolic extracts from cells expressing either active Ras or Akt. Akt phosphorylated recombinant Casp9 in vitro on serine-196 and inhibited its protease activity. Mutant pro-Casp9(Ser196Ala) was resistant to Akt-mediated phosphorylation and inhibition in vitro and in cells, resulting in Akt-resistant induction of apoptosis. Thus, caspases can be directly regulated by protein phosphorylation.

  • * These authors contributed equally to this work.

  • Present address: Department of Biology, MIT, Cambridge, MA 02139, USA.

  • To whom correspondence should be addressed at The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. E-mail: jreed{at}

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