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 Sarbassov, Mien Chie Hung, Keiichi I. Nakayama, Hui Kuan Lin

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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 (US)
Pages (from-to)1098-1111
Number of pages14
JournalCell
Volume149
Issue number5
DOIs
StatePublished - May 25 2012

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Ubiquitin-Protein Ligases
Ubiquitination
Glycolysis
TNF Receptor-Associated Factor 6
Carcinogenesis
Chemical activation
Insulin-Like Growth Factor I
Breast Neoplasms
Tumors
Neoplasms
Epidermal Growth Factor
Intercellular Signaling Peptides and Proteins
Phosphotransferases
Neoplasm Metastasis
Glucose
Membranes
Cell growth
Therapeutics
Growth
Metabolism

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Chan, C. H., Li, C. F., Yang, W. L., Gao, Y., Lee, S. W., Feng, Z., ... Lin, H. K. (2012). The Skp2-SCF E3 ligase regulates akt ubiquitination, glycolysis, herceptin sensitivity, and tumorigenesis. Cell, 149(5), 1098-1111. https://doi.org/10.1016/j.cell.2012.02.065

The Skp2-SCF E3 ligase regulates akt ubiquitination, glycolysis, herceptin sensitivity, and tumorigenesis. / Chan, Chia Hsin; Li, Chien Feng; Yang, Wei Lei; Gao, Yuan; Lee, Szu Wei; Feng, Zizhen; Huang, Hsuan Ying; Tsai, Kelvin K.C.; Flores, Leo G.; Shao, Yiping; Hazle, John D.; Yu, Dihua; Wei, Wenyi; Sarbassov, Dos; Hung, Mien Chie; Nakayama, Keiichi I.; Lin, Hui Kuan.

In: Cell, Vol. 149, No. 5, 25.05.2012, p. 1098-1111.

Research output: Contribution to journalArticle

Chan, CH, Li, CF, Yang, WL, Gao, Y, Lee, SW, Feng, Z, Huang, HY, Tsai, KKC, Flores, LG, Shao, Y, Hazle, JD, Yu, D, Wei, W, Sarbassov, D, Hung, MC, Nakayama, KI & Lin, HK 2012, 'The Skp2-SCF E3 ligase regulates akt ubiquitination, glycolysis, herceptin sensitivity, and tumorigenesis', Cell, vol. 149, no. 5, pp. 1098-1111. https://doi.org/10.1016/j.cell.2012.02.065
Chan, Chia Hsin ; Li, Chien Feng ; Yang, Wei Lei ; Gao, Yuan ; Lee, Szu Wei ; Feng, Zizhen ; Huang, Hsuan Ying ; Tsai, Kelvin K.C. ; Flores, Leo G. ; Shao, Yiping ; Hazle, John D. ; Yu, Dihua ; Wei, Wenyi ; Sarbassov, Dos ; Hung, Mien Chie ; Nakayama, Keiichi I. ; Lin, Hui Kuan. / The Skp2-SCF E3 ligase regulates akt ubiquitination, glycolysis, herceptin sensitivity, and tumorigenesis. In: Cell. 2012 ; Vol. 149, No. 5. pp. 1098-1111.
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