Anti-apoptotic signaling of the insulin-like growth factor-I receptor through mitochondrial translocation of c-Raf and Nedd4

The type 1 insulin-like growth factor receptor (IGF-IR) sends a strong anti -apoptotic signal by at least three different pathways. By using mutants of the IGF-IR, we showed that one of the pathways depends on residues of the IGF-IR (serines 1280-1283) that interact with 14.3.3 proteins. The result i s the activation of Raf-1 and the mitochondrial translocation of both Raf-1 and Nedd4, a target of caspases. A mutant IGF-IR in which the serines at p ositions 1280-1283 have been mutated to alanine does not protect from apopt osis and fails to translocate Nedd4 or Raf-1 to the mitochondria. This fail ure is accompanied by a loss of cytochrome c from the mitochondria, The 14. 3.3/Raf-1/Nedd4 pathway is operative in the presence or absence of the insu lin receptor substrate-1.