Cleavage of epidermal growth factor receptor by caspase during apoptosis is independent of its internalization
Cleavage of epidermal growth factor receptor by caspase during apoptosis is independent of its internalization
复制标题
DOI：
10.1038/sj.onc.1209184
复制
发表时间：
2006-03-01
期刊：
影响因子：
8
通讯作者：
Chignell, CF
中科院分区：
文献类型：
--
作者：
He, YY;Huang, JL;Chignell, CF
表皮生长因子受体（EGFR）在细胞增殖、分化和转化中起关键作用。EGFR下调减弱其信号强度和持续时间以维持细胞内稳态。在这里，我们报告说，在细胞凋亡EGFR裂解活化的caspase-3或相关蛋白酶在其C-末端结构域。通过激活半胱天冬酶的EGFR下调既不是刺激特异性的，也不是细胞类型特异性的。细胞凋亡过程中EGFR的内化需要发动蛋白和胆固醇，因为显性负性发动蛋白（K44 A）或胆固醇消耗甲基-β-环糊精阻止EGFR的内化。然而，EGFR下调并不需要其内化。除细胞团块外，在膜泡中检测到EGFR切割片段。在C端结构域的共有序列（DXXD）处的突变揭示DVVD 1012和在较小程度上DNPD 1172可能是体外活性重组胱天蛋白酶-3和体内活化胱天蛋白酶-3或相关蛋白酶的靶位点。我们已经在体外和体内检测到N-末端和C-末端片段。一种切割缺陷型EGFR突变体延迟了凋亡过程。我们的结论是，进化保守的EGFR的C-末端结构域是半胱天冬酶的目标，并在细胞凋亡过程中进行降解，关闭其信号转导。
Epidermal growth factor receptor ( EGFR) plays a critical role in cell proliferation, differentiation, and transformation. EGFR downregulation attenuates its signaling intensity and duration to maintain cellular homeostasis. Here, we report that during apoptosis EGFR is cleaved by activated caspase-3 or related proteases at its C-terminus domain. EGFR downregulation by activation of caspases is neither stimulus- nor cell type-specific. EGFR internalization during apoptosis required dynamin and cholesterol since dominant-negative dynamin (K44A) or cholesterol depletion by methyl-beta-cyclodextrin prevented EGFR internalization. However, EGFR downregulation did not require its internalization. The EGFR cleavage fragment was detected in the membrane blebs in addition to the cell pellets. Mutations at the consensus sequence (DXXD) at the C-terminus domain revealed that DVVD1012 and to a lesser extent DNPD1172 may be target sites for active recombinant caspase-3 in vitro and activated caspase-3 or related proteases in vivo. We have detected the N-terminus and C-terminus fragments in vitro and in vivo. A cleavage-deficient EGFR mutant delayed apoptosis process. We conclude that the evolutionarily conserved C-terminus domain of EGFR is the target of caspases and subjected to degradation during apoptosis to shut down its signaling.