Induction of cancer cell migration by epidermal growth factor is initiated by specific phosphorylation of tyrosine 1248 of c-erbB-2 receptor via epidermal growth factor receptor
Induction of cancer cell migration by epidermal growth factor is initiated by specific phosphorylation of tyrosine 1248 of c-erbB-2 receptor via epidermal growth factor receptor
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DOI：
10.1096/fj.02-0096fje
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发表时间：
2002-09-01
期刊：
影响因子：
4.8
通讯作者：
Brandt, BH
中科院分区：
文献类型：
--
作者：
Dittmar, T;Husemann, A;Brandt, BH
诱导肿瘤细胞迁移是侵袭和转移的关键步骤。在此，我们报道表皮生长因子 (EGF) 诱导的乳腺癌细胞迁移归因于 c-erbB-2 信号传导导致的磷脂酶 C (PLC)-gamma1 的短暂激活，而不是持续激活。 EGF 刺激 EGF 受体 (EGFR) 过表达细胞，导致长期 PLC-gamma1 酪氨酸磷酸化和持续水平的肌醇 1,4,5-三磷酸 (IP3) 和二酰甘油 (DAG)，从而产生正弦钙振荡。相比之下，c-erbB-2/EGFR 表达细胞在 EGF 处理后由于短期 PLC-gamma1 酪氨酸磷酸化和短期 IP3 和 DAG 更新而表现出基线瞬时钙振荡。生成了表达缺乏自磷酸化 Y1248 的点突变 c-erbB-2 受体的第三个细胞系，以研究不同的 PLC-gamma1 激活是否归因于此结构。在此细胞系中未观察到 PLC-gamma1 酪氨酸磷酸化、IP3 和 DAG 更新以及钙振荡，表明 c-erbB-2 信号传导对 PLC-gamma1 激活时间过程的调节。细胞迁移的诱导仅在 c-erbB-2 阳性细胞系中观察到，如肌动蛋白重组模式和使用 3D 胶原晶格的细胞迁移测定所证明的。总之，c-erbB-2 上调通过调节 PLC-gamma1 激活的时间过程来开启细胞迁移程序。
Induction of tumor cell migration is a key step in invasion and metastasis. Here we report that the epidermal growth factor (EGF)-induced cell migration of breast cancer cells is attributed to a transient, rather than a sustained, activation of phospholipase C (PLC)-gamma1 due to c-erbB-2 signaling. EGF stimulation of EGF receptor (EGFR) overexpressing cells resulted in long-term PLC-gamma1 tyrosine phosphorylation and sustained levels of inositol-1,4,5-triphosphate (IP3) and diacylglycerol (DAG) producing sinusoidal calcium oscillations. In contrast, c-erbB-2/EGFR expressing cells displayed baseline transient calcium oscillations after EGF treatment due to short-term PLC-gamma1 tyrosine phosphorylation and short-term IP3 and DAG turnover. A third cell line expressing a point-mutated c-erbB-2 receptor that lacks the autophosphorylation Y1248 was generated to investigate whether the different PLC-gamma1 activation was attributed to this structure. Neither PLC-gamma1 tyrosine phosphorylation nor IP3 and DAG turnover and calcium oscillations were observed in this cell line, indicating the modulation of the PLC-gamma1 activation time course by c-erbB-2 signaling. Induction of cell migration was solely observable in the c-erbB-2-positive cell line as proved by the mode of actin reorganization and a cell migration assay, using a 3D-collagen lattice. In summary, c-erbB-2 up-regulation switches on the cell migration program by modulating the time course of PLC-gamma1 activation.