title: Cbl-b-dependent coordinated degradation of the epidermal growth factor receptor signaling complex.
abstract: Cbl proteins function as ubiquitin protein ligases for the activated epidermal growth factor receptor and, thus, negatively regulate its activity. Here we show that Cbl-b is ubiquitinated and degraded upon activation of the receptor. Epidermal growth factor (EGF)-induced Cbl-b degradation requires intact RING finger and tyrosine kinase binding domains and requires binding of the Cbl-b protein to the activated EGF receptor (EGFR). Degradation of both the EGFR and the Cbl-b protein is blocked by lysosomal and proteasomal inhibitors. Other components of the EGFR-signaling complex (i.e. Grb2 and Shc) are also degraded in an EGF-induced Cbl-b-dependent fashion. Our results suggest that the ubiquitin protein ligase function of Cbl-b is regulated by coordinated degradation of the Cbl-b protein along with its substrate. Furthermore, the data demonstrate that Cbl-b mediates degradation of multiple proteins in the EGFR-signaling complex.
authors.affiliation: Genetics Department of the Medicine Branch and the Laboratory of Immune Cell Biology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20889, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Ettenberg
authors.forename: A
authors.initials: A
authors.lastname: Magnifico
authors.forename: M
authors.initials: M
authors.lastname: Cuello
authors.forename: M M
authors.initials: MM
authors.lastname: Nau
authors.forename: Y R
authors.initials: YR
authors.lastname: Rubinstein
authors.forename: Y
authors.initials: Y
authors.lastname: Yarden
authors.forename: A M
authors.initials: AM
authors.lastname: Weissman
authors.forename: S
authors.initials: S
authors.lastname: Lipkowitz
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins / Q000737:chemistry / Q000502:physiology*; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D010750:Phosphoproteins / Q000737:chemistry / Q000502:physiology*; D011487:Protein Conformation; D050721:Proto-Oncogene Proteins c-cbl; D015398:Signal Transduction / Q000502:physiology*; D014407:Tumor Cells, Cultured; D044767:Ubiquitin-Protein Ligases; D014452:Ubiquitins / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D010750:Phosphoproteins; D014452:Ubiquitins; C492211:CBLB protein, human; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D066246:ErbB Receptors