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WW domain HECT E3s target Cbl RING finger E3s for proteasomal degradation

  1. Author:
    Magnifico, A.
    Ettenberg, S.
    Yang, C. H.
    Mariano, J.
    Tiwari, S.
    Fang, S. Y.
    Lipkowitz, S.
    Weissman, A. M.

  2. Author Address

    NCI, Regulat Prot Funct Lab, Ctr Canc Res, Bldg 560,Rm 22-102, Frederick, MD 21702 USA NCI, Regulat Prot Funct Lab, Ctr Canc Res, Frederick, MD 21702 USA NCI, Cellular & Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20817 USA Weissman AM NCI, Regulat Prot Funct Lab, Ctr Canc Res, Bldg 560,Rm 22-102, Frederick, MD 21702 USA
    1. Year: 2003
  2. Journal: Journal of Biological Chemistry
    1. 278
    2. 44
    3. Pages: 43169-43177
  4. Type of Article: Article
  1. Abstract:

    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.

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