The WW domain containing E3 ubiquitin protein ligase 1 upregulates ErbB2 and EGFR through RING finger protein 11
The WW domain containing E3 ubiquitin protein ligase 1 upregulates ErbB2 and EGFR through RING finger protein 11
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DOI：
10.1038/onc.2008.288
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发表时间：
2008-11-20
期刊：
影响因子：
8
通讯作者：
Seth, A. K.
中科院分区：
文献类型：
--
作者：
Chen, C.;Zhou, Z.;Seth, A. K.
包含WW结构域的E3泛素蛋白连接酶1（WWP 1）与E6相关蛋白C末端型E3连接酶同源，该连接酶由于基因扩增而经常在人前列腺癌和乳腺癌中过表达。以前的研究表明，WWP 1促进细胞增殖和存活;然而，WWP 1的作用机制仍然知之甚少。在这里，我们发现，WWP 1上调和维持成红细胞白血病病毒癌基因同源物2（ErbB 2）和上皮生长因子受体（EGFR）在多个细胞系。WWP 1缺失显著减弱EGF诱导的ERK磷酸化。WWP 1与RING指蛋白11（RNF 11）形成蛋白复合物，RNF 11是ErbB 2和EGFR的负调节因子。蛋白质相互作用是通过WWP 1的第一和第三WW结构域和RNF 11的PY基序。虽然WWP 1能够在体外和体内泛素化RNF 11，但WWP 1既不靶向RNF 11降解，也不改变RNF 11的细胞定位。重要的是，抑制RNF 11可以挽救WWP 1 siRNA诱导的ErbB 2和EGFR下调和生长停滞。最后，我们证明了RNF 11在一组表达WWP 1的前列腺癌和乳腺癌细胞系中过表达。这些结果表明，WWP 1可能通过抑制RNF 11介导的ErbB 2和EGFR下调，部分促进细胞增殖和存活。Oncogene（2008）27，6845-6855; doi：10.1038/onc.2008.288; 2008年8月25日在线公开
The WW domain containing E3 ubiquitin protein ligase 1 (WWP1) is a homologous to the E6-associated protein C terminus-type E3 ligase frequently overexpressed in human prostate and breast cancers due to gene amplification. Previous studies suggest that WWP1 promotes cell proliferation and survival; however, the mechanism of WWP1 action is still poorly understood. Here, we showed that WWP1 upregulates and maintains erythroblastic leukemia viral oncogene homolog 2 (ErbB2) and epithelial growth factor receptor (EGFR) in multiple cell lines. WWP1 depletion dramatically attenuates the EGF-induced ERK phosphorylation. WWP1 forms a protein complex with RING finger protein 11 (RNF11), a negative regulator of ErbB2 and EGFR. The protein protein interaction is through the first and third WW domains of WWP1 and the PY motif of RNF11. Although WWP1 is able to ubiquitinate RNF11 in vitro and in vivo, WWP1 neither targets RNF11 for degradation nor changes RNF11's cellular localization. Importantly, inhibition of RNF11 can rescue WWP1 siRNA-induced ErbB2 and EGFR downregulation and growth arrest. Finally, we demonstrated that RNF11 is overexpressed in a panel of prostate and breast cancer cell lines with WWP1 expression. These findings suggest that WWP1 may promote cell proliferation and survival partially through suppressing RNF11-mediated ErbB2 and EGFR downregulation. Oncogene (2008) 27, 6845-6855; doi: 10.1038/onc.2008.288; published online 25 August 2008