Identification of EGF receptor C-terminal sequences 1005-1017 and di-leucine motif 1010LL1011 as essential in EGF receptor endocytosis
Identification of EGF receptor C-terminal sequences 1005-1017 and di-leucine motif 1010LL1011 as essential in EGF receptor endocytosis
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DOI：
10.1016/j.yexcr.2007.06.014
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发表时间：
2007-09-10
影响因子：
3.7
通讯作者：
Wang, Zhixiang
中科院分区：
文献类型：
--
作者：
Wang, Qian;Zhu, Fuxiang;Wang, Zhixiang
大多数关于表皮生长因子 (EGF) 受体 (EGFR) C 端结构域在 EGFR 内化中的作用的研究都是在 EGFR 激酶激活的背景下进行的。我们最近表明，EGF 诱导的 EGFR 内化直接受受体二聚化控制，而不是激酶激活。在这里，我们研究了 EGFR C 末端在 EGF 诱导的 EGFR 内化（有或没有 EGFR 激酶激活）中的作用。我们发现，无论有或没有激酶激活，EGFR 从 C 端逐渐截短至 1044 都不影响 EGF 诱导的 EGFR 内吞作用。然而，截短至991或进一步完全抑制EGFR内吞作用。 991-1044内的梯度截断逐渐降低EGF诱导的EGFR内吞作用，并在残基1005-1017观察到最显着的影响。突变型 EGFR 的内吞模式与 EGFR 激酶激活无关。残基 1005-1017 也是由非配体诱导的受体二聚化触发的 EGFR 内化所必需的。这表明残基1005-1017充当内化基序而不是二聚化基序来介导EGFR内化。此外，我们发现该区域内的二亮氨酸基序 (LL1011)-L-1010 对于介导 EGF 诱导的快速 EGFR 内化至关重要，而与激酶激活无关。我们得出结论，EGFR C 端序列 1005-1017 和 1010LL1011 基序对于 EGF 诱导的 EGFR 内吞作用至关重要，与 EGFR 激酶激活和自磷酸化无关。 (c) 2007 Elsevier Inc. 保留所有权利。
Most studies regarding the role of epidermal growth factor (EGF) receptor (EGFR) C-terminal domain in EGFR internalization are done in the context of EGFR kinase activation. We recently showed that EGF-induced EGFR internalization is directly controlled by receptor dimerization, rather than kinase activation. Here we studied the role of EGFR C-terminus in EGF-induced EGFR internalization with or without EGFR kinase activation. We showed that graduate truncation of EGFR from C-terminus to 1044 did not affect EGF-induced EGFR endocytosis with or without kinase activation. However, truncation to 991 or further completely inhibited EGFR endocytosis. Graduate truncation within 991-1044 progressively lower EGF-induced EGFR endocytosis with most significant effects observed for residues 1005-1017. The endocytosis patterns of mutant EGFRs are independent of EGFR kinase activation. The residues 1005-1017 were also required for EGFR internalization triggered by non-ligand-induced receptor dimerization. This indicates that residues 1005-1017 function as an internalization motif, rather than a dimerization motif, to mediate EGFR internalization. Furthermore, we showed that the di-leucine motif (LL1011)-L-1010 within this region is essential in mediating EGF-induced rapid EGFR internalization independent of kinase activation. We conclude that EGFR C-terminal sequences 1005-1017 and the 1010LL1011 motif are essential for EGF-induced EGFR endoytosis independent of EGFR kinase activation and autophosphorylation. (c) 2007 Elsevier Inc. All rights reserved.