The Skp2-SCF E3 ligase regulates akt ubiquitination, glycolysis, herceptin sensitivity, and tumorigenesis

Chia Hsin Chan, Chien Feng Li, Wei Lei Yang, Yuan Gao, Szu Wei Lee, Zizhen Feng, Hsuan Ying Huang, Kelvin K C Tsai, Leo G. Flores, Yiping Shao, John D. Hazle, Dihua Yu, Wenyi Wei, Dos D. Sarbassov, Mien Chie Hung, Keiichi I. Nakayama, Hui Kuan Lin

研究成果: 雜誌貢獻文章同行評審

260 引文 斯高帕斯(Scopus)

摘要

Akt kinase plays a central role in cell growth, metabolism, and tumorigenesis. The TRAF6 E3 ligase orchestrates IGF-1-mediated Akt ubiquitination and activation. Here, we show that Akt ubiquitination is also induced by activation of ErbB receptors; unexpectedly, and in contrast to IGF-1 induced activation, the Skp2 SCF complex, not TRAF6, is a critical E3 ligase for ErbB-receptor-mediated Akt ubiquitination and membrane recruitment in response to EGF. Skp2 deficiency impairs Akt activation, Glut1 expression, glucose uptake and glycolysis, and breast cancer progression in various tumor models. Moreover, Skp2 overexpression correlates with Akt activation and breast cancer metastasis and serves as a marker for poor prognosis in Her2-positive patients. Finally, Skp2 silencing sensitizes Her2-overexpressing tumors to Herceptin treatment. Our study suggests that distinct E3 ligases are utilized by diverse growth factors for Akt activation and that targeting glycolysis sensitizes Her2-positive tumors to Herceptin treatment.
原文英語
頁(從 - 到)1098-1111
頁數14
期刊Cell
149
發行號5
DOIs
出版狀態已發佈 - 5月 25 2012
對外發佈

ASJC Scopus subject areas

  • 生物化學、遺傳與分子生物學 (全部)

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