The Skp2-SCF E3 Ligase Regulates Akt Ubiquitination, Glycolysis, Herceptin Sensitivity, and Tumorigenesis

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2012 May 29

PMID 22632973

Citations 225

Authors

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

Affiliations

Soon will be listed here.

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.

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