An essential role for Src kinase in ErbB receptor signaling through the MAPK pathway
An essential role for Src kinase in ErbB receptor signaling through the MAPK pathway
复制标题
DOI：
10.1006/excr.2001.5242
复制
发表时间：
2001-07-01
影响因子：
3.7
通讯作者：
Hynes, NE
中科院分区：
文献类型：
--
作者：
Olayioye, MA;Badache, A;Hynes, NE
ErbB受体酪氨酸激酶被多种配体激活，如表皮生长因子（EGF）和神经调节因子（NRGs），导致细胞内信号通路的刺激，包括丝裂原活化蛋白激酶（MAPK）级联。我们发现，当低浓度的配体刺激乳腺癌细胞系T47D和SKBR3时，Src激酶对于EGF-和nrg诱导的MAPK的快速激活至关重要。在特异性阻断Src家族激酶活性的药理学抑制剂CGP77675存在的情况下，配体诱导的MAPK激活在5分钟后几乎完全被阻断。尽管这种阻滞只是短暂的，Src的失活抑制了配体诱导的mapk响应启动子的转录。在分子水平上，Src失活对MAPK的初始抑制与配体诱导的Shc磷酸化受损相关，令人惊讶的是，Src抑制既不影响Shc与ErbB受体的关联，也不影响受体结合的Shc的磷酸化。因此，ErbB信号需要一个新的src依赖的MAPK通路，以触发其快速激活和随后有效的转录刺激。(C) 2001学术出版社。
ErbB receptor tyrosine kinases are activated by multiple ligands such as epidermal growth factor (EGF) and neuregulins (NRGs), leading to stimulation of intracellular signaling pathways, including the mitogen-activated protein kinase (MAPK) cascade. We show here that Src kinase is essential for rapid EGF- and NRG-induced MAPK activation when the breast carcinoma cell lines T47D and SKBR3 are stimulated with low concentrations of ligand, In the presence of the pharmacological inhibitor CGP77675, which specifically blocks the activity of Src family kinases, ligand-induced MAPK activation was almost completely blocked at 5 min. Although this block was only transient, inactivation of Src suppressed ligand-induced transcription from a MAPK-responsive promoter. At the molecular level, the initial inhibition of MAPK by Src inactivation correlated with impaired ligand-induced Shc phosphorylation, Surprisingly, Src inhibition affected neither association of Shc with ErbB receptors nor phosphorylation of receptor-bound Shc. Thus, ErbB signaling requires the engagement of a novel Src-dependent route to MAPK, to trigger its rapid activation and subsequent efficient stimulation of transcription. (C) 2001 Academic Press.