Enhanced internalization of ErbB2 in SK-BR-3 cells with multivalent forms of an artificial ligand.
Enhanced internalization of ErbB2 in SK-BR-3 cells with multivalent forms of an artificial ligand.
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DOI：
10.1111/j.1582-4934.2011.01277.x
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发表时间：
2011-11
影响因子：
5.3
通讯作者：
Seno M
中科院分区：
文献类型：
--
作者：
Vaidyanath A;Hashizume T;Nagaoka T;Takeyasu N;Satoh H;Chen L;Wang J;Kasai T;Kudoh T;Satoh A;Fu L;Seno M
EGF受体家族成员ErbB 2在乳腺癌和卵巢癌细胞中过表达，因此靶向下调ErbB 2被认为是肿瘤治疗的关键之一。虽然还没有发现ErbB 2的天然配体，但与其他ErbB受体不同，EC-1是一种20个氨基酸的环状肽，已被证明可以作为人工配体与ErbB 2结合。先前我们显示EC-1肽在SK-BR-3细胞中不诱导ErbB 2的内化。在这份报告中，我们设计了二价和多价形式的EC-1肽，其中人IgG的Fc部分和生物纳米胶囊在其表面上用ZZ-标签修饰，以改善与ErbB 2的相互作用。这些形式对ErbB 2的亲和力比EC-1单体更高。此外，当用生物纳米胶囊表面上多价展示的EC-Fc配体刺激时，在SK-BR-3细胞中发生ErbB 2的显著内体积累，而SK-BR-3细胞本身在没有刺激的情况下显示出针对ErbB 2内化的严格机制。EC-1肽的多价形式似乎比二价形式更有效地内化ErbB 2。这种内化不受网格蛋白结合抑制的影响，但当胆固醇耗尽时受到抑制，这解释了小窝或GPI-AP-早期内吞隔室（GEEC）途径。SK-BR-3细胞中由于caveolin-1表达的缺失，导致细胞膜小窝机制的丧失。因此，这表明EC-1的多价形式通过GEEC途径诱导ErbB 2的内化。
Targeting and down-regulation of ErbB2, a member of EGF receptor family, is regarded as one of the key aspect for cancer treatment because it is often overexpressed in breast and ovarian cancer cells. Although natural ligands for ErbB2 have not been found, unlike other ErbB receptors, EC-1, a 20-amino acid circular peptide, has been shown to bind to ErbB2 as an artificial ligand. Previously we showed EC-1 peptide did not induce the internalization of ErbB2 in SK-BR-3 cells. In this report, we designed divalent and multivalent forms of EC-1 peptide with the Fc portion of the human IgG and bionanocapsule modified with ZZ-tag on its surface to improve the interaction with ErbB2. These forms showed higher affinity to ErbB2 than that of EC-1 monomer. Furthermore, prominent endosomal accumulation of ErbB2 occurred in SK-BR-3 cells when stimulated with EC-Fc ligand multivalently displayed on the surface of the bionanocapsule, whereas SK-BR-3 cells as themselves displayed stringent mechanism against ErbB2 internalization without stimulation. The multivalent form of EC-1 peptide appeared to internalize ErbB2 more efficiently than divalent form did. This internalization was unaffected by the inhibition of clathrin association, but inhibited when the cholesterol was depleted which explained either caveolar or GPI-AP-early endocytic compartment (GEEC) pathway. Because of the lack of caveolin-1 expression, caveolar machinery may be lost in SK-BR-3 cell line. Therefore, it is suggested that the multivalent form of EC-1 induces the internalization of ErbB2 through the GEEC pathway.
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DOI：
10.1023/a:1019749504418
发表时间：
2002-05-01
期刊：
JOURNAL OF PROTEIN CHEMISTRY
影响因子：
--
作者：
Karasseva, NG;Glinsky, VV;Quinn, TP
通讯作者：
Quinn, TP
DOI：
10.1073/pnas.0409610102
发表时间：
2005-02-08
影响因子：
11.1
作者：
Friedman, LM;Rinon, A;Yarden, Y
通讯作者：
Yarden, Y
影响因子：
9.2
作者：
Mills, IG;Jones, AT;Clague, MJ
通讯作者：
Clague, MJ
影响因子：
3.9
作者：
Hashizume, Toshihiro;Fukuda, Takayuki;Seno, Masaharu
通讯作者：
Seno, Masaharu
影响因子：
3.3
作者：
Hommelgaard, AM;Lerdrup, M;van Deurs, B
通讯作者：
van Deurs, B