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 is 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 positions 1280--1283 have been mutated to alanine does not protect from apoptosis and fails to translocate Nedd4 or Raf-1 to the mitochondria. This failure 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 insulin receptor substrate-1.
Peruzzi
F
F
Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Prisco
M
M
Morrione
A
A
Valentinis
B
B
Baserga
R
R
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001692:Biological Transport / Q000502:physiology; D002135:Calcium-Binding Proteins / Q000502:physiology*; D002460:Cell Line; D056827:Endosomal Sorting Complexes Required for Transport; D008025:Ligases / Q000502:physiology*; D051379:Mice; D008928:Mitochondria / Q000502:physiology; D000075702:Nedd4 Ubiquitin Protein Ligases; D019908:Proto-Oncogene Proteins c-raf / Q000502:physiology*; D017526:Receptor, IGF Type 1 / Q000502:physiology*; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases
D002135:Calcium-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618461:Nedd4l protein, mouse; D044767:Ubiquitin-Protein Ligases; D017526:Receptor, IGF Type 1; D019908:Proto-Oncogene Proteins c-raf; D008025:Ligases