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.
Highlights
Insulin-like growth factor I (IGF-I) plays an important role in cell survival, proliferation, and differentiation
Based on the fact that receptor-interacting protein (RIP) is involved in Jun N-terminal kinase (JNK) activation by different stimulations, we explored the possible role of RIP in IGF-I-induced JNK activation with RIPϪ/Ϫ mouse embryonic fibroblast (MEF) cells as a cell model
Because comparable expression levels of JNK1 and IGF-I receptor (IGF-IR) were detected in both RIPϪ/Ϫ and wild type (WT) cells (Fig. 1B, second and fourth panels), it is unlikely that the decrease of JNK activation in RIPϪ/Ϫ cells resulted from the altered expression of JNK or the IGF-IR
Summary
Insulin-like growth factor I (IGF-I) plays an important role in cell survival, proliferation, and differentiation. The results indicate that the death domain kinase RIP, a key factor in TNF signaling, plays a pivotal role in the IGF-IR-mediated activation of JNK. RIPϪ/Ϫ cells were confirmed by Western blot analysis to be null of RIP and defective to TNF-induced JNK activation by an in vitro kinase assay (Fig. 1B and data not shown).
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call