Differential Roles of Grb2 and AP-2 in p38 MAPK- and EGF-Induced EGFR Internalization
Differential Roles of Grb2 and AP-2 in p38 MAPK- and EGF-Induced EGFR Internalization
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DOI：
10.1111/j.1600-0854.2011.01322.x
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发表时间：
2012-04-01
期刊：
影响因子：
4.5
通讯作者：
van Deurs, Bo
中科院分区：
文献类型：
--
作者：
Grandal, Michael V.;Grovdal, Lene M.;van Deurs, Bo
表皮生长因子受体（epidermal growth factor receptor， EGFR）是细胞正常生长和分化的重要调节因子，参与多种癌症的发生。配体刺激后，内吞下调是终止EGFR信号传导的关键。p38 MAPK的激活也可以诱导EGFR内吞作用。这种内吞作用缺乏配体诱导的EGFR内吞作用的许多特征。我们比较了两种类型的内吞作用对蛋白质的内化机制的要求。两种类型的内吞作用都需要网格蛋白，但表皮生长因子（EGF）诱导的EGFR内化也需要Grb2，而p38 mapk诱导的内化则不需要。有趣的是，AP-2敲除阻断了p38 mapk诱导的EGFR内化，但仅轻度影响egf诱导的内化。与此一致，同时突变EGFR中两个AP-2相互作用位点对p38 mapk诱导的内化的影响远大于egf诱导的EGFR内化。因此，两种情况下的EGFR似乎使用了不同的内化机制。
The epidermal growth factor receptor (EGFR) is an important regulator of normal growth and differentiation, and it is involved in the pathogenesis of many cancers. Endocytic downregulation is central in terminating EGFR signaling after ligand stimulation. It has been shown that p38 MAPK activation also can induce EGFR endocytosis. This endocytosis lacks many of the characteristics of ligand-induced EGFR endocytosis. We compared the two types of endocytosis with regard to the requirements for proteins in the internalization machinery. Both types of endocytosis require clathrin, but while epidermal growth factor (EGF)-induced EGFR internalization also required Grb2, p38 MAPK-induced internalization did not. Interestingly, AP-2 knock down blocked p38 MAPK-induced EGFR internalization, but only mildly affected EGF-induced internalization. In line with this, simultaneously mutating two AP-2 interaction sites in EGFR affected p38 MAPK-induced internalization much more than EGF-induced EGFR internalization. Thus, it seems that EGFR in the two situations uses different sets of internalization mechanisms.