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The Skp2-SCF E3 ligase regulates Akt ubiquitination, glycolysis, herceptin sensitivity, and tumorigenesis |
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| Authors: | 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 |
| Institution: | 1 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 2 Department of Experimental Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 3 Department of Image Physics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 4 The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA 5 Department of Pathology, Chi-Mei Foundational Medical Center, Tainan 710, Taiwan 6 National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan 7 Department of Pathology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung County 833, Taiwan 8 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA 9 Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan 10 Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University and Hospital, Taichung 404, Taiwan 11 Department of Biotechnology, Southern Taiwan University, Tainan 710, Taiwan |
| 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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