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

Research output: Contribution to journalArticlepeer-review

220 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1098-1111
Number of pages14
JournalCell
Volume149
Issue number5
DOIs
Publication statusPublished - May 25 2012
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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