The Skp2-SCF E3 ligase regulates Akt ubiquitination, glycolysis, herceptin sensitivity, and tumorigenesis.
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.
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Chia-Hsin
CH
Chan
Chien-Feng
CF
Li
Wei-Lei
WL
Yang
Yuan
Y
Gao
Szu-Wei
SW
Lee
Zizhen
Z
Feng
Hsuan-Ying
HY
Huang
Kelvin K C
KK
Tsai
Leo G
LG
Flores
Yiping
Y
Shao
John D
JD
Hazle
Dihua
D
Yu
Wenyi
W
Wei
Dos
D
Sarbassov
Mien-Chie
MC
Hung
Keiichi I
KI
Nakayama
Hui-Kuan
HK
Lin
D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D044783:F-Box Proteins / Q000378:metabolism*; D005260:Female; D006019:Glycolysis; D006801:Humans; D051379:Mice; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D000068878:Trastuzumab; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D054875:Ubiquitination
D061067:Antibodies, Monoclonal, Humanized; D044783:F-Box Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D044786:S-Phase Kinase-Associated Proteins; D000068878:Trastuzumab; D025521:Tumor Suppressor Proteins; C507917:FBXO31 protein, human