WW domain-containing proteins, WWOX and YAP, compete for interaction with ErbB-4 and modulate its transcriptional function
WW domain-containing proteins, WWOX and YAP, compete for interaction with ErbB-4 and modulate its transcriptional function
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DOI：
10.1158/0008-5472.can-05-1150
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发表时间：
2005-08-01
期刊：
影响因子：
11.2
通讯作者：
Croce, CM
中科院分区：
文献类型：
--
作者：
Aqeilan, RI;Donati, V;Croce, CM
含有WW结构域的氧化还原酶（WWOX）是一种肿瘤抑制因子，在几种癌症类型中被删除或改变。我们最近发现WWOX与p73和AP-2 γ相互作用并抑制它们的转录活性。yes相关蛋白（Yes-associated protein， YAP）也含有WW结构域，可与p73结合并增强其转录活性。此外，YAP与ErbB-4受体酪氨酸激酶相互作用，并作为ErbB-4的cooh末端片段（CTF）的转录辅激活因子。用12- o - tetradecanoylpholl -13-acetate （TPA）刺激表达erbb -4的细胞，导致其细胞质结构域的蛋白水解裂解和该结构域向细胞核的易位。在这里，我们报道了WWOX通过其第一个WW结构域与全长ErbB-4物理结合。在HeLa细胞中，经TPA处理后，WWOX和ErbB-4的共表达导致ErbB-4在细胞质中保留。此外，在表达高水平内源性WWOX的MCF-7乳腺癌细胞中，内源性ErbB-4也保留在细胞质中。此外，我们的研究结果表明，WWOX和ErbB-4的相互作用以剂量依赖的方式抑制YAP对CTF的转录协同激活。缺乏与ErbB-4相互作用的WWOX突变体形式对ErbB-4的共激活没有影响。此外，WWOX能够抑制YAP对p73的共激活。综上所述，我们的数据表明，WWOX通过与ErbB-4和其他靶点竞争相互作用来拮抗YAP的功能，从而影响其转录活性。
The WW domain-containing oxidoreductase, WWOX, is a tumor suppressor that is deleted or altered in several cancer types. We recently showed that WWOX interacts with p73 an AP-2 gamma and suppresses their transcriptional activity. Yes-associated protein (YAP), also containing WW domains, was shown to associate with p73 and enhance its transcriptional activity. In addition, YAP interacts with ErbB-4 receptor tyrosine kinase and acts as transcriptional coactivator of the COOH-terminal fragment (CTF) of ErbB-4. Stimulation of ErbB-4-expressing cells with 12-O-tetradecanoylphorbol-13-acetate (TPA) results in the proteolytic cleavage of its cytoplasmic domain and translocation of this domain to the nucleus. Here we report that WWOX physically associates with the full-length ErbB-4 via its first WW domain. Coexpression of WWOX and ErbB-4 in HeLa cells followed by treatment with TPA results in the retention of ErbB-4 in the cytoplasm. Moreover, in MCF-7 breast carcinoma cells, expressing high levels of endogenous WWOX, endogenous ErbB-4 is also retained in the cytoplasm. In addition, our results show that interaction of WWOX and ErbB-4 suppresses transcriptional coactivation of CTF by YAP in a dose-dependent manner. A mutant form of WWOX lacking interaction with ErbB-4 has no effect on this coactivation of ErbB-4. Furthermore, WWOX is able to inhibit coactivation of p73 by YAP. In summary, our data indicate that WWOX antagonizes the function of YAP by competing for interaction with ErbB-4 and other targets and thus affect its transcriptional activity.