Insulin-like growth factor-I signaling in human neuroblastoma cells
Insulin-like growth factor-I signaling in human neuroblastoma cells
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DOI：
10.1038/sj.onc.1206924
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发表时间：
2004-01-08
期刊：
影响因子：
8
通讯作者：
Feldman, EL
中科院分区：
文献类型：
--
作者：
Kim, B;van Golen, CM;Feldman, EL
神经母细胞瘤是一种由N(神经元)和S(间质)细胞组成的异质性肿瘤。我们报告了更多的致瘤性和运动性的N细胞表达更高水平的胰岛素样生长因子-I受体(IGFIR)，而更少的致瘤性和更多的黏附的S细胞。SHC是胰岛素样生长因子-IR的两个主要对接伙伴之一，在N和S细胞系中表达相同。胰岛素样生长因子-I可使N细胞Shc磷酸化，但对S细胞Shc仅有微弱的激活作用。第二个伙伴胰岛素受体底物(IRS)的表达是细胞类型特异性的。S细胞独有表达胰岛素样生长因子-1，经胰岛素样生长因子-I持续磷酸化。相反，N细胞表达被IGF-I短暂磷酸化的IRS-2。在IRS-2和Shc的下游，IGF-I治疗导致N细胞Akt和MAPK的强烈激活，这两个通路的激活是IGF-I介导的分化所必需的。在粘着斑激酶和帕西林的刺激下，N和S细胞的肿瘤边缘皱褶只需要磷脂酰肌醇-3激酶的IGFIR激活。对N和S细胞‘生化特征’的详细了解为靶向和干扰特定的胰岛素样生长因子信号通路，试图开发更有效的治疗方法提供了所需的背景知识。
Neuroblastoma is a heterogeneous tumor consisting of N (neuronal) and S (stromal) cells. We report that more tumorigenic and motile N cells express higher levels of IGF-I receptor (IGF-IR) than less tumorigenic, more adherent S cells. Shc, one of the two major docking partners of IGF-IR, is equally expressed in N and S cell lines. IGF-I treatment phosphorylates Shc in N cells, but only weakly activates Shc in S cells. Expression of the second partner, insulin receptor substrate (IRS), is cell type specific. S cells exclusively express IRS-1 that undergoes sustained phosphorylation by IGF-I. In contrast, N cells express IRS-2 that is transiently phosphorylated by IGF-I. Downstream of IRS-2 and Shc, IGF-I treatment results in strong activation of Akt and MAPK in N cells and activation of both pathways is required for IGF-I-mediated differentiation. Only IGF-IR activation of phosphatidylinositol-3 kinase is required for tumor edge ruffling in N and S cells, with stimulation of focal adhesion kinase (FAK) and paxillin. This detailed understanding of the 'biochemical signature' of N and S cells provides the background needed to target and disrupt specific IGF signaling pathways in an attempt to develop more effective therapies.