Activation of extracellular signal-regulated kinase by ultraviolet is mediated through Src-dependent epidermal growth factor receptor phosphorylation - Its implication in an anti-apoptotic function
Activation of extracellular signal-regulated kinase by ultraviolet is mediated through Src-dependent epidermal growth factor receptor phosphorylation - Its implication in an anti-apoptotic function
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DOI：
10.1074/jbc.m107110200
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发表时间：
2002-01-04
影响因子：
4.8
通讯作者：
Katada, T
中科院分区：
文献类型：
--
作者：
Kitagawa, D;Tanemura, S;Katada, T
紫外线（UV）照射刺激应激活化蛋白激酶/c-Jun N-末端激酶（SAPK/ JNK），其是促分裂原活化蛋白激酶（MAPK）超家族的成员，并且与应激诱导的细胞凋亡有关。UV还诱导另一MAPK成员细胞外信号调节激酶（ERK）的活化，其通常参与生长信号级联。然而，导致ERK激活的紫外线诱导的信号通路及其生理作用仍然未知。在这里，我们研究了紫外线诱导的ERK激活的人表皮样癌A431细胞，保留了大量的表皮生长因子（EGF）受体的分子机制和生理功能。UV诱导的ERK激活伴随着EGF受体的Tyr磷酸化，并且在选择性EGF受体抑制剂（AG 1478）或Src抑制剂PP 2的存在下以及通过表达激酶死亡的Src突变体，这两种反应都被完全废除。另一方面，SAPK/JNK的激活由UV部分抑制这些抑制剂。UV刺激Src活性的方式类似于ERK激活，但Src激活对AG 1478不敏感。通过DNA片段化和caspase 3激活测量的UV诱导的细胞凋亡被AG 1478和ERK激酶抑制剂（U 0126）增强，但被激动剂EGF受体刺激抑制。这些结果表明，紫外线诱导的ERK激活，这提供了一个生存信号，对应力诱导的细胞凋亡，介导的Src依赖性酪氨酸磷酸化的EGF受体。
Ultraviolet (UV) irradiation stimulates stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/ JNK), which is a member of the mitogen-activated protein kinase (MAPK) superfamily and implicated in stress-induced apoptosis. UV also induces the activation of another MAPK member, extracellular signal-regulated kinase (ERK), which is typically involved in a growth-signaling cascade. However, the UV-induced signaling pathway leading to ERK activation, together with the physiological role, has remained unknown. Here we examined the molecular mechanism and physiological function of UV-induced ERK activation in human epidermoid carcinoma A431 cells that retain a high number of epidermal growth factor (EGF) receptors. UV-induced ERK activation was accompanied with the Tyr phosphorylation of EGF receptors, and both responses were completely abolished in the presence of a selective EGF receptor inhibitor (AG1478) or the Src inhibitor PP2 and by the expression of a kinase-dead Src mutant. On the other hand, SAPK/JNK activation by UV was partially inhibited by these inhibitors. UV stimulated Src activity in a manner similar to the ERK activation, but the Src activation was insensitive to AG1478. UV-induced cell apoptosis measured by DNA fragmentation and caspase 3 activation was enhanced by AG1478 and an ERK kinase inhibitor (U0126) but inhibited by EGF receptor stimulation by the agonist. These results indicate that UV-induced ERK activation, which provides a survival signal against stress-induced apoptosis, is mediated through Src-dependent Tyr phosphorylation of EGF receptors.