NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN.
The tumor suppressor PTEN, a critical regulator for multiple cellular processes, is mutated or deleted frequently in various human cancers. Subtle reductions in PTEN expression levels have profound impacts on carcinogenesis. Here we show that PTEN level is regulated by ubiquitin-mediated proteasomal degradation, and purified its ubiquitin ligase as HECT-domain protein NEDD4-1. In cells NEDD4-1 negatively regulates PTEN stability by catalyzing PTEN polyubiquitination. Consistent with the tumor-suppressive role of PTEN, overexpression of NEDD4-1 potentiated cellular transformation. Strikingly, in a mouse cancer model and multiple human cancer samples where the genetic background of PTEN was normal but its protein levels were low, NEDD4-1 was highly expressed, suggesting that aberrant upregulation of NEDD4-1 can posttranslationally suppress PTEN in cancers. Elimination of NEDD4-1 expression inhibited xenotransplanted tumor growth in a PTEN-dependent manner. Therefore, NEDD4-1 is a potential proto-oncogene that negatively regulates PTEN via ubiquitination, a paradigm analogous to that of Mdm2 and p53.
Wang
Xinjiang
X
Cell Biology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 522, New York, NY 10021, USA.
Trotman
Lloyd C
LC
Koppie
Theresa
T
Alimonti
Andrea
A
Chen
Zhenbang
Z
Gao
Zhonghua
Z
Wang
Junru
J
Erdjument-Bromage
Hediye
H
Tempst
Paul
P
Cordon-Cardo
Carlos
C
Pandolfi
Pier Paolo
PP
Jiang
Xuejun
X
D000818:Animals; D002471:Cell Transformation, Neoplastic; D056827:Endosomal Sorting Complexes Required for Transport; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D000075702:Nedd4 Ubiquitin Protein Ligases; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D025821:Polyubiquitin / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D000090063:Proto-Oncogene Mas; D011519:Proto-Oncogenes; D034622:RNA Interference; D013379:Substrate Specificity; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000172:deficiency / Q000302:isolation & purification / Q000378:metabolism*
D056827:Endosomal Sorting Complexes Required for Transport; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D025821:Polyubiquitin; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; C000618461:Nedd4l protein, mouse; D044767:Ubiquitin-Protein Ligases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C487757:Pten protein, mouse