The essential role of the death domain kinase receptor-interacting protein in insulin growth factor-I-induced c-Jun N-terminal kinase activation.
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.
Lin
Yong
Y
Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108, USA. ylin@lrri.org
Yang
Qingfeng
Q
Wang
Xia
X
Liu
Zheng-gang
ZG
D000818:Animals; D016923:Cell Death / Q000502:physiology; D002460:Cell Line; D049109:Cell Proliferation; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D006801:Humans; D047468:Immunoprecipitation; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017434:Protein Structure, Tertiary / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000502:physiology; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D015398:Signal Transduction / Q000502:physiology; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D048049:Extracellular Signal-Regulated MAP Kinases; D007334:Insulin-Like Growth Factor I; D048031:JNK Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; C506249:RIPK1 protein, human; C506251:Ripk1 protein, mouse