Src tyrosine kinase inhibitor PP2 suppresses ERK1/2 activation and epidermal growth factor receptor transactivation by X-irradiation
Src tyrosine kinase inhibitor PP2 suppresses ERK1/2 activation and epidermal growth factor receptor transactivation by X-irradiation
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DOI：
10.1016/j.bbrc.2005.12.193
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发表时间：
2006-03-10
影响因子：
3.1
通讯作者：
Miyagawa, K
中科院分区：
文献类型：
--
作者：
Li, ZP;Hosoi, Y;Miyagawa, K
MDA-MB-468细胞暴露于电离辐射（IR）引起ERK的双相活化，如其在Thr 202/Tyr 204处的磷酸化所示。特异性表皮生长因子受体（EGFR）抑制剂AG 1478和特异性Src抑制剂PP 2抑制IR诱导的ERK 1/2激活，但磷脂酰肌醇-3激酶抑制剂渥曼青霉素没有。IR引起EGFR酪氨酸磷酸化，而它不诱导EGFR在Tyr 992，Tyr 1045和Tyr 1068处的自磷酸化或在Tyr 845处的Si-c依赖性EGFR磷酸化。SHP-2正调节EGFR/Ras/ERK信号级联，如其在Tyr 542处的磷酸化所示，被IR激活。这种激活被PP 2抑制，而不是被AG 1478抑制，这表明SHP-2的Si-c依赖性激活。Src和正调节Src的PTP α分别被磷酸化Lit Tyr 416和Tyr 789激活。这些数据表明，IR诱导的ERK 1/2活化涉及EGFR通过Src依赖性途径，这是从EGFR配体活化不同。
Exposure of MDA-MB-468 cells to ionizing radiation (I R) caused biphasic activation of ERK as indicated by its phosphorylation at Thr202/Tyr204. Specific epidermal growth factor receptor (EGFR) inhibitor AG 1478 and specific Src inhibitor PP2 inhibited IR-induced ERK1/2 activation but phosphatidylinositol-3 kinase inhibitor wortmannin did not. IR caused EGFR tyrosine phosphorylation, whereas it did not induce EGFR autophosphorylation at Tyr992, Tyr1045, and Tyr1068 or Si-c-dependent EGFR phosphorylation at Tyr845. SHP-2, which positively regulates EGFR/Ras/ERK signaling cascade, became activated by IR as indicated by its phosphorylation at Tyr542. This activation was inhibited by PP2 not by AG1478, which suggests Si-c-dependent activation of SHP-2. Src and PTP alpha, which positively regulates Src, became activated as indicated by phosphorylation Lit Tyr416 and Tyr789, respectively. These data suggest that IR-induced ERK1/2 activation involves EGFR through a Src-dependent pathway that is distinct from EGFR ligand activation.