Regulation of EGFR Protein Stability by the HECT-type Ubiquitin Ligase SMURF2
Regulation of EGFR Protein Stability by the HECT-type Ubiquitin Ligase SMURF2
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DOI：
10.1593/neo.11632
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发表时间：
2011-07-01
期刊：
影响因子：
4.8
通讯作者：
Nyati, Mukesh K.
中科院分区：
文献类型：
--
作者：
Ray, Dipankar;Ahsan, Aarif;Nyati, Mukesh K.
表皮生长因子受体（EGFR）在多种上皮性肿瘤中过表达，被认为是重要的治疗靶点。尽管基因扩增是某些人类恶性肿瘤（包括肺癌和头颈癌）中EGFR过表达的原因，但可能存在其他分子机制。在这里，我们报告了一种新的相互作用的EGFR与HECT型泛素连接酶SMURF 2，它可以泛素化，但稳定EGFR保护它从c-Cbl介导的降解。相反，小干扰RNA（siRNA）介导的SMURF 2敲低使EGFR不稳定，诱导自噬反应并降低EGFR表达癌细胞系的克隆形成存活率，对EGFR阴性癌细胞、正常成纤维细胞和正常上皮细胞的影响最小。UMSCC 74 B头颈部鳞状细胞癌细胞在裸鼠中形成侵袭性肿瘤，在siRNA介导的SMURF 2敲低后显著丧失体内肿瘤形成能力。来自443名肺腺癌患者的基因表达微阵列数据和来自67名此类患者的组织微阵列数据分别显示EGFR和SMURF 2在信使RNA和蛋白质水平上的表达之间的强相关性。我们的研究结果表明，SMURF 2介导的EGFR保护性泛素化可能是某些肿瘤中EGFR过表达的原因，并支持靶向SMURF 2-EGFR相互作用作为治疗EGFR成瘾肿瘤的新治疗方法。
Epidermal growth factor receptor (EGFR) is overexpressed in a variety of epithelial tumors and is considered to be an important therapeutic target. Although gene amplification is responsible for EGFR overexpression in certain human malignancies including lung and head and neck cancers, additional molecular mechanisms are likely. Here, we report a novel interaction of EGFR with an HECT-type ubiquitin ligase SMURF2, which can ubiquitinate, but stabilize EGFR by protecting it from c-Cbl-mediated degradation. Conversely, small interfering RNA (siRNA)-mediated knockdown of SMURF2 destabilized EGFR, induced an autophagic response and reduced the clonogenic survival of EGFR-expressing cancer cell lines, with minimal effects on EGFR-negative cancer cells, normal fibroblasts, and normal epithelial cells. UMSCC74B head and neck squamous cancer cells, which form aggressive tumors in nude mice, significantly lost in vivo tumor-forming ability on siRNA-mediated SMURF2 knockdown. Gene expression microarray data from 443 lung adenocarcinoma patients, and tissue microarray data from 67 such patients, showed a strong correlation of expression between EGFR and SMURF2 at the messenger RNA and protein levels, respectively. Our findings suggest that SMURF2-mediated protective ubiquitination of EGFR may be responsible for EGFR overexpression in certain tumors and support targeting SMURF2-EGFR interaction as a novel therapeutic approach in treating EGFR-addicted tumors.