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| Content Provider | PubMed Central |
|---|---|
| Author | Lin, Qiong Wang, Jian Childress, Chandra Sudol, Marius Carey, David J. Yang, Wannian |
| Copyright Year | 2010 |
| Abstract | ACK (activated Cdc42-associated tyrosine kinase) (also Tnk2) is an ubiquitin-binding protein and plays an important role in ligand-induced and ubiquitination-mediated degradation of epidermal growth factor receptor (EGFR). Here we report that ACK is ubiquitinated by HECT E3 ubiquitin ligase Nedd4-1 and degraded along with EGFR in response to EGF stimulation. ACK interacts with Nedd4-1 through a conserved PPXY WW-binding motif. The WW3 domain in Nedd4-1 is critical for binding to ACK. Although ACK binds to both Nedd4-1 and Nedd4-2 (also Nedd4L), Nedd4-1 is the E3 ubiquitin ligase for ubiquitination of ACK in cells. Interestingly, deletion of the sterile alpha motif (SAM) domain at the N terminus dramatically reduced the ubiquitination of ACK by Nedd4-1, while deletion of the Uba domain dramatically enhanced the ubiquitination. Use of proteasomal and lysosomal inhibitors demonstrated that EGF-induced ACK degradation is processed by lysosomes, not proteasomes. RNA interference (RNAi) knockdown of Nedd4-1, not Nedd4-2, inhibited degradation of both EGFR and ACK, and overexpression of ACK mutants that are deficient in either binding to or ubiquitination by Nedd4-1 blocked EGF-induced degradation of EGFR. Our findings suggest an essential role of Nedd4-1 in regulation of EGFR degradation through interaction with and ubiquitination of ACK. |
| Related Links | http://dx.doi.org/10.1128/mcb.00013-10 |
| Ending Page | 1554 |
| Page Count | 14 |
| Starting Page | 1541 |
| File Format | |
| ISSN | 02707306 |
| e-ISSN | 10985549 |
| Journal | Molecular and Cellular Biology |
| Issue Number | 6 |
| Volume Number | 30 |
| Language | English |
| Publisher | American Society for Microbiology (ASM) |
| Publisher Date | 2010-03-15 |
| Access Restriction | Open |
| Rights Holder | American Society for Microbiology (ASM) |
| Subject Keyword | Cell Biology Molecular Biology Research in Higher Education |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Molecular Biology |
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