Crucial role of the C-terminus of PTEN in antagonizing NEDD4-1-mediated PTEN ubiquitination and degradation Journal Article
| Authors: | Wang, X.; Shi, Y.; Wang, J.; Huang, G.; Jiang, X. |
| Article Title: | Crucial role of the C-terminus of PTEN in antagonizing NEDD4-1-mediated PTEN ubiquitination and degradation |
| Abstract: | 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. © 2008 Biochemical Society. |
| Keywords: | controlled study; human cell; nonhuman; binding affinity; protein domain; protein function; protein analysis; animal cell; animals; carboxy terminal sequence; embryo; protein degradation; protein protein interaction; cell line; protein binding; protein stability; cell assay; molecular mechanics; regulatory mechanism; ubiquitination; amino terminal sequence; tumors; recombinant proteins; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; pten phosphohydrolase; spodoptera; protein structure, tertiary; catalysis; amino acids; animal cell culture; sequence homology; ubiquitin protein ligase nedd4; ubiquitin-protein ligases; enzymes; tryptophan; protein e6; degradation; mechanisms; stability; port terminals; cancer mutation; neural-precursor-cell-expressed developmentally down-regulated 4-1 (nedd4-1); phosphatase and tensin homologue deleted on chromosome 10 (pten) |
| Journal Title: | Biochemical Journal |
| Volume: | 414 |
| Issue: | 2 |
| ISSN: | 0264-6021 |
| Publisher: | Portland Press Ltd |
| Date Published: | 2008-09-01 |
| Start Page: | 221 |
| End Page: | 229 |
| Language: | English |
| DOI: | 10.1042/bj20080674 |
| PUBMED: | 18498243 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 13" - "Export Date: 17 November 2011" - "CODEN: BIJOA" - "Source: Scopus" |
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