This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Li, X. Articles by Yao, L. Search for Related Content PubMed PubMed Citation Articles by Li, X. Articles by Yao, L.

Degradation of HER2 by Cbl-Based Chimeric Ubiquitin Ligases

¹ State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology; ² Department of Medical Genetics and Developmental Biology; and ³ Biotechnology Center, The Fourth Military Medical University, Xi'an, China

Requests for reprints: Libo Yao, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China. Phone: 86-29-84774513; Fax: 86-29-84774513; E-mail: bioyao{at}fmmu.edu.cn and Wei Han, Biotechnology Center, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China. E-mail: hanwwcn{at}yahoo.com.cn.

Targeting disease-causing proteins for ubiquitination and degradation by chimeric molecules represents a promising alternative therapeutic strategy in cancer. Here, several Cbl-based chimeric ubiquitin ligases were recombined to achieve effective down-regulation of HER2. These chimeric molecules consisted of the Cbl NH₂-terminal tyrosine kinase binding domain, linker, and RING domain, with the Src homology 2 domain replaced with that from growth factor receptor binding protein 2 (Grb2), Grb7, p85, or Src. The chimeric proteins not only interacted with HER2 but also enhanced the down-regulation of endogenous overexpressed HER2. After the chimeric proteins were introduced into HER2-overexpressing breast cancer SK-BR-3 cells or ovarian cancer SK-OV-3 cells, they effectively promoted HER2 ubiquitination and degradation in a RING finger domain–dependent manner. Consequently, expression of these chimeric molecules led to an inhibition of colony formation, increased the proportion of cells in the G₁ cycle, and suppressed tumorigenicity. Collectively, our findings suggest that the Cbl-based chimeric ubiquitin ligases designed in the present study may represent a novel approach for the targeted therapy of HER2-overexpressing cancers. [Cancer Res 2007;67(18):8716–24]