PTEN (phosphatase and tensin homologue deleted on chromosome 10), a potent tumour suppressor and multifunctional signalling protein, is under intricate regulation. In the present study, we have investigated the mechanism and regulation of PTEN ubiquitination catalysed by NEDD4-1 (neural-precursor-cell-expressed, developmentally down-regulated 4-1), a ubiquitin ligase for PTEN we identified recently. Using the reconstituted assay and cellular analysis, we demonstrated that NEDD4-1-mediated PTEN ubiquitination depends on its intact HECT (homologous to E6-associated protein C-terminus) domain. Instead of using its WW domains (protein–protein interaction domains containing two conserved tryptophan residues) as a protein interaction module, NEDD4-1 interacts with PTEN through its N-terminal region containing a C2 domain as well as the HECT domain. Strikingly, we found that a C-terminal truncated PTEN fragment binds to NEDD4-1 with higher affinity than the full-length PTEN, suggesting an intrinsic inhibitory effect of the PTEN C-terminus on PTEN–NEDD4-1 interaction. Moreover, the C-terminal truncated PTEN is more sensitive to NEDD4-1-mediated ubiquitination and degradation. Therefore the present study reveals that the C-terminus of PTEN plays a critical role in stabilizing PTEN via antagonizing NEDD4-1-induced PTEN protein decay; conversely, truncation of the PTEN C-terminus results in rapid NEDD4-1-mediated PTEN degradation, a possible mechanism accounting for attenuation of PTEN function by certain PTEN mutations in human cancers.
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Research Article|
August 12 2008
Crucial role of the C-terminus of PTEN in antagonizing NEDD4-1-mediated PTEN ubiquitination and degradation
Xinjiang Wang;
Xinjiang Wang
1Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, U.S.A.
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Yuji Shi;
Yuji Shi
1Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, U.S.A.
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Junru Wang;
Junru Wang
1Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, U.S.A.
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Guochang Huang;
Guochang Huang
1Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, U.S.A.
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Xuejun Jiang
Xuejun Jiang
1
1Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, U.S.A.
1To whom correspondence should be addressed (email jiangx@mskcc.org).
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Publisher: Portland Press Ltd
Received:
March 28 2008
Revision Received:
May 13 2008
Accepted:
May 22 2008
Accepted Manuscript online:
May 22 2008
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2008 Biochemical Society
2008
Biochem J (2008) 414 (2): 221–229.
Article history
Received:
March 28 2008
Revision Received:
May 13 2008
Accepted:
May 22 2008
Accepted Manuscript online:
May 22 2008
Citation
Xinjiang Wang, Yuji Shi, Junru Wang, Guochang Huang, Xuejun Jiang; Crucial role of the C-terminus of PTEN in antagonizing NEDD4-1-mediated PTEN ubiquitination and degradation. Biochem J 1 September 2008; 414 (2): 221–229. doi: https://doi.org/10.1042/BJ20080674
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