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HECT E3 ubiquitin ligase Nedd4-1 ubiquitinates ACK and regulates epidermal growth factor (EGF)-induced degradation of EGF receptor and ACK.

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.

Pubmed ID: 20086093

Authors

  • Lin Q
  • Wang J
  • Childress C
  • Sudol M
  • Carey DJ
  • Yang W

Journal

Molecular and cellular biology

Publication Data

March 2, 2010

Associated Grants

None

Mesh Terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Cell Line
  • Conserved Sequence
  • Endosomal Sorting Complexes Required for Transport
  • Epidermal Growth Factor
  • Gene Knockdown Techniques
  • Humans
  • Lysosomes
  • Mice
  • Molecular Sequence Data
  • Mutant Proteins
  • Proteasome Endopeptidase Complex
  • Protein Binding
  • Protein Processing, Post-Translational
  • Protein Structure, Tertiary
  • Protein-Tyrosine Kinases
  • Receptor, Epidermal Growth Factor
  • Signal Transduction
  • Ubiquitin-Protein Ligases
  • Ubiquitination