@article{3a094c46c29743dc95b90284dba381d7,
title = "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.",
author = "Chan, {Chia Hsin} and Li, {Chien Feng} and Yang, {Wei Lei} and Yuan Gao and Lee, {Szu Wei} and Zizhen Feng and Huang, {Hsuan Ying} and Tsai, {Kelvin K C} and Flores, {Leo G.} and Yiping Shao and Hazle, {John D.} and Dihua Yu and Wenyi Wei and Sarbassov, {Dos D.} and Hung, {Mien Chie} and Nakayama, {Keiichi I.} and Lin, {Hui Kuan}",
note = "Funding Information: We thank Mrs. J. Delacerda and C.V. Kingsley at small animal imaging facility of MD Anderson Cancer Center for their assistance in CT/PET imaging. We also thank the members from Lin's laboratory for their valuable comments and suggestions. We thank Drs. W. Tansey and M. H. Lee for reagents. This work was supported by the MD Anderson Cancer Center Trust Scholar Award, Prostate SPORE Career Development Award (P50 CA140388 SPORE), NIH grants, CPRIT grant, DOD prostate cancer New Investigator Award (H.K.L.), the MD Anderson Cancer Center Breast SPORE Career Development Award (C.H.C.), the Susan G. Komen Breast Cancer Foundation postdoctoral fellowship (C.H.C.), and a grant from the Department of Health in Taiwan (C.F.L.). ",
year = "2012",
month = may,
day = "25",
doi = "10.1016/j.cell.2012.02.065",
language = "English",
volume = "149",
pages = "1098--1111",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "5",
}
