The essential role of the death domain kinase receptor-interacting protein in insulin growth factor-I-induced c-Jun N-terminal kinase activation
The essential role of the death domain kinase receptor-interacting protein in insulin growth factor-I-induced c-Jun N-terminal kinase activation
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DOI：
10.1074/jbc.m601487200
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发表时间：
2006-08-18
影响因子：
4.8
通讯作者：
Liu, Zheng-gang
中科院分区：
文献类型：
--
作者：
Lin, Yong;Yang, Qingfeng;Liu, Zheng-gang
胰岛素样生长因子I（IGF-I）在细胞存活、增殖和分化中起重要作用。IGF-I可激活多种激酶，包括AKT/蛋白激酶B、细胞外信号调节激酶（ERK）和c-Jun N-末端激酶（JNK）。在这里，我们表明，受体相互作用蛋白（RIP），肿瘤坏死因子诱导的NF-κ B和JNK激活的关键介质，在IGF-I受体信号转导中起着关键作用。IGF-I在野生型小鼠胚胎成纤维细胞中诱导稳健的JNK活化，但在RIP无效（RIP-/-）小鼠胚胎成纤维细胞中不诱导。RIP-/-细胞中RIP表达的重建恢复了IGF-I对JNK的诱导，表明RIP在IGF-I诱导的JNK激活中是必不可少的。用不同RIP突变体的重建实验进一步揭示RIP的死亡结构域和激酶活性对于IGF-I诱导的JNK活化不是必需的。有趣的是，在RIP-/-细胞中，IGF-I对AKT和ERK的激活是正常的。磷脂酰肌醇3激酶抑制剂渥曼青霉素不影响IGF-I诱导的JNK激活。这些结果与先前的研究一致，表明IGF-I诱导的JNK活化途径不同于ERK和AKT活化途径。此外，异位表达RIP和IGF-IR β的物理相互作用通过免疫共沉淀试验检测。更重要的是，RIP在IGF-I诱导的信号传导过程中被募集到IGF-I受体复合物中。此外，我们发现IGF-I诱导的细胞增殖受损RIP-/-细胞。综上所述，我们的研究结果表明，RIP，在肿瘤坏死因子信号转导的关键因素，也发挥了关键作用IGF-I诱导的JNK激活和细胞增殖。
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-kappa B 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-IR beta 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.