Expression of herstatin, an autoinhibitor of HER-2/neu, inhibits transactivation of HER-3 by HER-2 and blocks EGF activation of the EGF receptor
Expression of herstatin, an autoinhibitor of HER-2/neu, inhibits transactivation of HER-3 by HER-2 and blocks EGF activation of the EGF receptor
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DOI：
10.1038/sj.onc.1204555
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发表时间：
2001-08-23
期刊：
影响因子：
8
通讯作者：
Clinton, GM
中科院分区：
文献类型：
--
作者：
Azios, NG;Romero, FJ;Clinton, GM
EGF受体家族的四个成员既可以是同聚体，也可以是异构体。HER-2/neu(erbB-2)是增强有丝分裂信号的首选辅助受体。另一种HER-2/neu产物Herstatin由p185HER-2的胞外结构域片段和内编码的C末端组成。重组Herstatin能与nm亲和力结合并抑制p185HER-2。为了进一步研究Herstatin对受体活性的影响，用不同的受体酪氨酸激酶表达Herstatin。在过度表达HER-2的CHO细胞中，Herstatin对克隆形成的抑制作用是7倍，这与p185HER-2的酪氨酸磷酸化减少相对应。Herstatin还阻止了HER-2介导的激酶反式激活损害了HER-3，这反映在HER-3和HER-2和HER-3之间的异构体的转磷酸化上。在EGF受体过表达的细胞中，EGF对受体二聚化和酪氨酸磷酸化的诱导作用降低了90%以上，与Herstatin共表达也抑制了受体下调和集落形成。抑制EGF受体家族是有选择性的，因为Herstatin的表达不会减少由成纤维细胞生长因子受体-2或胰岛素样生长因子-1介导的酪氨酸磷酸化。在下拉实验中，Herstatin与EGF受体和p185HER-2结合，表明复合体的形成可能参与了受体的抑制。我们的发现表明，Herstatin能够负向调节I组受体酪氨酸激酶之间的相互作用组合，从而提供协同生长信号。
The four members of the EGF receptor family are capable of homomeric as well as heteromeric interactions. HER-2/neu (erbB-2) dominates as the preferred coreceptor that amplifies mitogenic signaling. An alternative HER-2/neu product, herstatin, consists of a segment of the ectodomain of p185HER-2 and an intronencoded C-terminus. Recombinant herstatin was found to bind with nm affinity and inhibit p185HER-2. To further examine the impact on receptor activity, herstatin was expressed with various receptor tyrosine kinases. In CHO cells that overexpressed HER-2, herstatin caused a sevenfold inhibition of colony formation that corresponded to a reduction in the tyrosine phosphorylation of p185HER-2. Herstatin also prevented HER-2 mediated transactivation of the kinase impaired HER-3 as reflected in transphosphorylation of HER-3 and heteromers between HER-2 and HER-3. In EGF receptor-overexpressing cells, EGF induction of receptor dimerization and tyrosine phosphorylation were reduced more than 90%, and receptor down-regulation as well as colony formation were also suppressed by coexpression with herstatin. Inhibition was selective for the EGF receptor family since herstatin expression did not reduce tyrosine phosphorylation mediated by the FGF receptor-2 or by insulin-like growth factor -1. Herstatin bound to the EGF receptor as well as to p185HER-2 in pull-down assays suggesting that complex formation may be involved in receptor inhibition. Our findings indicate that herstatin has the capability to negatively regulate combinations of interactions between group I receptor tyrosine kinases that confer synergistic growth signals.