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Nedd4 mediates ErbB4 JM-a/CYT-1 ICD ubiquitination and degradation in MDCK II cells

Zeng, Fenghua ; Xu, Jie ; Harris, Raymond C

The FASEB journal, 2009-06, Vol.23 (6), p.1935-1945 [Peer Reviewed Journal]

United States: The Federation of American Societies for Experimental Biology

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Title:
Nedd4 mediates ErbB4 JM-a/CYT-1 ICD ubiquitination and degradation in MDCK II cells
Author: Zeng, Fenghua ; Xu, Jie ; Harris, Raymond C
Subjects: Amino Acid Motifs ; Animals ; Cells, Cultured ; Dogs ; E3 ubiquitin ligase ; Endosomal Sorting Complexes Required for Transport ; Enzyme Inhibitors - metabolism ; Humans ; Lysosomes - metabolism ; Mutagenesis, Site-Directed ; Nedd4 Ubiquitin Protein Ligases ; nuclear translocation ; PI3 kinase ; Proteasome Endopeptidase Complex - metabolism ; Proteasome Inhibitors ; Protein Isoforms - genetics ; Protein Isoforms - metabolism ; Protein Structure, Tertiary ; PY motif mutation ; Receptor, Epidermal Growth Factor - genetics ; Receptor, Epidermal Growth Factor - metabolism ; Receptor, ErbB-4 ; Recombinant Fusion Proteins - genetics ; Recombinant Fusion Proteins - metabolism ; Research Communications ; Tetradecanoylphorbol Acetate - metabolism ; Ubiquitin - metabolism ; Ubiquitin-Protein Ligases - genetics ; Ubiquitin-Protein Ligases - metabolism ; Ubiquitination
Is Part Of: The FASEB journal, 2009-06, Vol.23 (6), p.1935-1945
Notes: Correspondence: C-3121 Medical Center North, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, 37232. E-mail: ray.harris@vanderbilt.edu
Description: ErbB4, a type I transmembrane receptor tyrosine kinase, is a member of the epidermal growth factor receptor family. Its cleavage releases an intracellular C-terminal domain (ICD), which can be either degraded following ubiqitination or translocated to the nucleus and regulate gene expression. There are 2 ErbB4 ICD isoforms: CYT-1 and CYT-2. We and others have previously reported that following cleavage, CYT-2 selectively translocates to the nucleus. In the current study we found that following cleavage, the intracellular levels of CYT-1 ICD decreased rapidly, while levels of CYT-2 ICD remained relatively stable. CYT-1 ICD degradation could be prevented by administration of either the proteasome inhibitor lactacystin or the lysosome inhibitor chloroquine, indicating both proteasomal and lysosomal degradation. Further studies implicated Nedd4, an E3 ubiquitin ligase, as a mediator of CYT-1 ubiquitination and degradation. The interaction of Nedd4 with CYT-1 was shown by coimmnunoprecipitation, an in vitro direct binding assay, and an in vitro ubiquitination assay. Three PPxY or PY motifs present in the CYT-1 C terminus are necessary for binding by Nedd4 WW domains, because impaired interactions are seen in mutation of any of the PY motifs. Nedd4-CYT-1 binding was associated with increased CYT-1 ubiquitination following proteasome inhibitor treatment. Impaired Nedd4 binding to CYT-1 by PY motif mutations led to increased CYT-1 ICD stability, whereas only one of the PY motif mutations (Y1056A), which disrupts the binding sites for both a WW domain and an SH2 domain of PI3 kinase, demonstrated enhanced nuclear translocation following HB-EGF treatment. These studies indicate that Nedd4 mediates ErbB4 CYT-1 ICD ubiquitination and degradation, and the prevention of both WW binding and PI3 kinase activity are required for ErbB4 nuclear translocation.--Zeng, F., Xu, J., Harris, R. C. Nedd4 mediates ErbB4 JM-a/CYT-1 ICD ubiquitination and degradation in MDCK II cells.
Publisher: United States: The Federation of American Societies for Experimental Biology
Language: English

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Nedd4 mediates ErbB4 JM-a/CYT-1 ICD ubiquitination and degradation in MDCK II cells

Zeng, Fenghua ; Xu, Jie ; Harris, Raymond C

United States: The Federation of American Societies for Experimental Biology

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