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

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.
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
Journal	Cell (Cell) Vol. 149 Issue 5 Pg. 1098-111 (May 25 2012) ISSN: 1097-4172 [Electronic] United States
PMID	22632973 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Copyright	Copyright © 2012 Elsevier Inc. All rights reserved.
Chemical References	Antibodies, Monoclonal, Humanized F-Box Proteins FBXO31 protein, human S-Phase Kinase-Associated Proteins Tumor Suppressor Proteins Receptor, ErbB-2 Trastuzumab
Topics	Animals Antibodies, Monoclonal, Humanized (therapeutic use) Breast Neoplasms (drug therapy, metabolism) Cell Transformation, Neoplastic Disease Models, Animal Drug Resistance, Neoplasm F-Box Proteins (metabolism) Female Glycolysis Humans Mice Receptor, ErbB-2 (metabolism) S-Phase Kinase-Associated Proteins (genetics, metabolism) Trastuzumab Tumor Suppressor Proteins (metabolism) Ubiquitination

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