The essential role of the death domain kinase receptor-interacting protein in insulin growth factor-I-induced c-Jun N-terminal kinase activation

J Biol Chem. 2006 Aug 18;281(33):23525-32. doi: 10.1074/jbc.M601487200. Epub 2006 Jun 22.

Abstract

Insulin-like growth factor I (IGF-I) plays an important role in cell survival, proliferation, and differentiation. Diverse kinases, including AKT/protein kinase B, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK), can be activated by IGF-I. Here, we show that the receptor-interacting protein (RIP), a key mediator of tumor necrosis factor-induced NF-kappaB and JNK activation, plays a key role in IGF-I receptor signaling. IGF-I induced a robust JNK activation in wild type but not RIP null (RIP-/-) mouse embryonic fibroblast cells. Reconstitution of RIP expression in the RIP-/- cells restored the induction of JNK by IGF-I, suggesting that RIP is essential in IGF-I-induced JNK activation. Reconstitution experiments with different RIP mutants further revealed that the death domain and the kinase activity of RIP are not required for IGF-I-induced JNK activation. Interestingly, the AKT and ERK activation by IGF-I was normal in RIP-/- cells. The phosphatidylinositol 3-kinase inhibitor, wortmannin, did not affect IGF-I-induced JNK activation. These results agree with previous studies showing that the IGF-I-induced JNK activation pathway is distinct from that of ERK and AKT activation. Additionally, physical interaction of ectopically expressed RIP and IGF-IRbeta was detected by co-immunoprecipitation assays. More importantly, RIP was recruited to the IGF-I receptor complex during IGF-I-induced signaling. Furthermore, we found that IGF-I-induced cell proliferation was impaired in RIP-/- cells. Taken together, our results indicate that RIP, a key factor in tumor necrosis factor signaling, also plays a pivotal role in IGF-I-induced JNK activation and cell proliferation.

MeSH terms

  • Animals
  • Cell Death / physiology
  • Cell Line
  • Cell Proliferation
  • Cells, Cultured
  • Enzyme Activation / physiology
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fibroblasts / enzymology
  • Fibroblasts / metabolism
  • Fibroblasts / physiology
  • Humans
  • Immunoprecipitation
  • Insulin-Like Growth Factor I / metabolism
  • Insulin-Like Growth Factor I / physiology*
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • Mice
  • Phosphatidylinositol 3-Kinases / physiology
  • Protein Structure, Tertiary / physiology
  • Protein-Serine-Threonine Kinases / deficiency
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Protein-Serine-Threonine Kinases / physiology*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptor, IGF Type 1 / physiology
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Signal Transduction / physiology
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / deficiency
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / genetics
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / metabolism
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / physiology*

Substances

  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
  • Insulin-Like Growth Factor I
  • Phosphatidylinositol 3-Kinases
  • Receptor, IGF Type 1
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • RIPK1 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk1 protein, mouse
  • Extracellular Signal-Regulated MAP Kinases
  • JNK Mitogen-Activated Protein Kinases