WW Domain HECT E3s Target Cbl RING Finger E3s for Proteasomal Degradation

Cbl proteins have RING finger-dependent ubiquitin ligase (E3) activity that is essential for down-regulation of tyrosine kinases. Here we establish that two WW domain HECT E3s, Nedd4 and Itch, bind Cbl proteins and target them for proteasomal degradation. This is dependent on the E3 activity of the...

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Bibliographic Details
Published in:The Journal of biological chemistry 2003-10, Vol.278 (44), p.43169-43177
Main Authors: Magnifico, Alessandra, Ettenberg, Seth, Yang, Cuihong, Mariano, Jennifer, Tiwari, Swati, Fang, Shengyun, Lipkowitz, Stan, Weissman, Allan M.
Format: Article
Language:English
Subjects:
Cell Line
Cysteine Endopeptidases - metabolism
Down-Regulation
Endosomal Sorting Complexes Required for Transport
Escherichia coli - metabolism
Glutathione Transferase - metabolism
Humans
Immunoblotting
Jurkat Cells
Multienzyme Complexes - metabolism
Nedd4 Ubiquitin Protein Ligases
Plasmids - metabolism
Precipitin Tests
Proteasome Endopeptidase Complex
Protein Binding
Protein Structure, Tertiary
Proto-Oncogene Proteins - metabolism
Proto-Oncogene Proteins c-cbl
Recombinant Fusion Proteins - metabolism
Repressor Proteins - metabolism
Time Factors
Transfection
Ubiquitin - metabolism
Ubiquitin-Protein Ligases - metabolism
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Summary:Cbl proteins have RING finger-dependent ubiquitin ligase (E3) activity that is essential for down-regulation of tyrosine kinases. Here we establish that two WW domain HECT E3s, Nedd4 and Itch, bind Cbl proteins and target them for proteasomal degradation. This is dependent on the E3 activity of the HECT E3s but not on that of Cbl. Consistent with these observations, in cells expressing the epidermal growth factor receptor, Nedd4 reverses Cbl-b effects on receptor down-regulation, ubiquitylation, and proximal events in signaling. Cbl-b also targets active Src for degradation in cells, and Nedd4 similarly reverses Cbl-mediated Src degradation. These findings establish that RING finger E3s can be substrates, not only for autoubiquitylation but also for ubiquitylation by HECT E3s and suggest an additional level of regulation for Cbl substrates including protein-tyrosine kinases.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M308009200