PC12 CELLS OVEREXPRESSING THE INSULIN-RECEPTOR UNDERGO INSULIN-DEPENDENT NEURONAL DIFFERENTIATION
PC12 CELLS OVEREXPRESSING THE INSULIN-RECEPTOR UNDERGO INSULIN-DEPENDENT NEURONAL DIFFERENTIATION
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DOI：
10.1016/s0960-9822(00)00155-x
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发表时间：
1994-08-01
期刊：
影响因子：
9.2
通讯作者：
LAX, I
中科院分区：
文献类型：
--
作者：
DIKIC, I;SCHLESSINGER, J;LAX, I
背景：神经生长因子刺激嗜铬细胞瘤PC12细胞生长停滞和神经元分化，而胰岛素诱导糖、脂代谢等多种代谢反应。此外，胰岛素和表皮生长因子都能刺激PC12细胞的增殖。尽管神经生长因子、胰岛素和表皮生长因子具有不同的生物学效应，但它们在PC12细胞中诱导的早期反应非常相似。神经生长因子的刺激导致丝裂原活化蛋白(MAP)激酶的持续激活和核转位。相比之下，胰岛素和表皮生长因子都可以诱导MAP激酶的瞬时激活，而不会导致该酶的核转位。结果：通过在PC12细胞中过表达胰岛素受体，我们观察到胰岛素依赖的轴突生长，这与神经生长因子在未转染和过度表达的细胞中诱导的生长相似。PC12细胞中胰岛素受体的过表达导致PC12细胞中胰岛素诱导的酪氨酸磷酸化蛋白的模式更加明显但相似，包括增强Grb2/SOS到与SHE或IRS1的复合体中的募集。高表达胰岛素受体的PC12细胞的MAP激活与NGF刺激PC12细胞的MAP激活相似：激活时间延长，并发生核移位。结论：胰岛素和NGF诱导MAP激活的亚细胞定位和持续时间的不同可能解释了这两种因子对PC12细胞不同的生物学作用。我们的结果表明，具有酪氨酸激酶活性的受体产生的信号的强度可以影响下游信号通路，导致细胞分化而不是细胞增殖。
Background: Stimulation of phaeochromocytoma PC12 cells by nerve growth factor leads to growth arrest and neuronal differentiation, whereas insulin induces various metabolic responses such as metabolism of glucose and lipids. Moreover, both insulin and epidermal growth factor stimulate the proliferation of PC12 cells. In spite of their different biological effects, nerve growth factor, insulin and epidermal growth factor induce very similar early responses in PC12 cells. Stimulation with nerve growth factor leads to the sustained activation and nuclear translocation of mitogen-activated protein (MAP) kinase. By contrast, both insulin and epidermal growth factor induce the transient activation of MAP kinase, without pronounced nuclear translocation of the enzyme. We have investigated whether the differential activation of signaling pathway components can account for the distinct cellular responses to these different growth factors.Results: By overexpressing insulin receptors in PC12 cells, we observed insulin-dependent neurite outgrowth, similar to that induced by nerve growth factor in both non-transfected and overexpressing cells. Overexpression of insulin receptors in PC12 cells leads to a more pronounced, but similar pattern of insulin-induced tyrosine-phosphorylated proteins in PC12 cells, including enhanced recruitment of Grb2/Sos into a complex with either She or IRS1. MAP kinase activation in response to insulin stimulation of cells overexpressing the insulin receptor is similar to MAP kinase activation in response to NGF stimulation of parental or overexpressing PC12 cells: the activation is prolonged and nuclear translocation of the enzyme occurs.Conclusion: The differential subcellular localization and duration of MAP kinase activation induced by insulin and NGF may explain the difference in the biological actions of these two factors on PC12 cells. Our results show that the strength of the signal generated by a receptor with tyrosine kinase activity can influence the downstream signaling pathway, leading to cell differentiation instead of cell proliferation.