Regulation of Cell Death Protease Caspase-9 by Phosphorylation

TLDR

Caspases are intracellular proteases that function as initiators and effectors of apoptosis. Akt and its activator p21‑Ras phosphorylate pro‑caspase‑9 on serine‑196, inhibiting its protease activity. Cytochrome‑c–induced processing of pro‑caspase‑9 is impaired in cells with active Ras or Akt, and a Ser196Ala mutant resists Akt phosphorylation and inhibition, demonstrating that caspases are directly regulated by phosphorylation.

Abstract

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.