Stabilization of AURKA by the E3 ubiquitin ligase CBLC in lung adenocarcinoma

Shiao Ya Hong, Yi Chun Lu, Shih Hsin Hsiao, Yu Rung Kao, Meng Hsuan Lee, Yi Ping Lin, Cheng Yi Wang, Cheng Wen Wu

研究成果: 雜誌貢獻文章同行評審

1 引文 斯高帕斯(Scopus)

摘要

CBL family proteins (CBL, CBLB and CBLC in mammals) are E3 ubiquitin ligases of protein tyrosine kinases. CBL mediates the lysosomal degradation of activated EGFR through K63-linked ubiquitination, while CBLC has an oncogenic function by positively regulating EGFR activation through K6 and K11-linked ubiquitination in EGFR mutant lung adenocarcinoma (LAD). Here, we used immunoprecipitation and mass spectrometry to study the CBLC interactome, and found that CBLC is also involved in cell cycle regulation by stabilizing Aurora kinase A (AURKA). CBLC interacted with the kinase domain of AURKA and positively regulated the stability of AURKA by conjugating monoubiquitination and K11/K63-linked polyubiquitination, which are protective from degrading K11/K48 polyubiquitination. CBLC depletion markedly decreased the half-life of AURKA in cycloheximide-treated LAD cells. When LAD cells were synchronized with double thymidine block at the G1/S boundary and then released into mitotic arrest, CBLC depletion delayed the accumulation and activation of AURKA and prevented cancer cells from entering mitosis. CBLC deficiency significantly delayed cell cycle progression, reduced the mitotic population, and increased apoptosis of LAD cells. Targeting CBLC inhibited tumor growth of LAD cells and enhanced their sensitivity to paclitaxel in xenograft models. Immunohistochemical staining of the tissue microarray also revealed a positive correlation between the expression of CBLC and AURKA in normal and LAD tissues, further supporting the positive regulation of AURKA expression by CBLC. In summary, these findings indicate that the oncogenic E3 ligase CBLC plays a role in mitotic entry by stabilizing AURKA via ubiquitination in LAD. This work demonstrates that targeting CBLC combined with paclitaxel might be a potential option for the treatment of LAD patients who have no available targeted therapies.
原文英語
頁(從 - 到)1907-1917
頁數11
期刊Oncogene
41
發行號13
DOIs
出版狀態已發佈 - 3月 25 2022

ASJC Scopus subject areas

  • 分子生物學
  • 遺傳學
  • 癌症研究

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