Cbl-b-dependent coordinated degradation of the epidermal growth factor receptor signaling complex.
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.
Ettenberg
S A
SA
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.
Magnifico
A
A
Cuello
M
M
Nau
M M
MM
Rubinstein
Y R
YR
Yarden
Y
Y
Weissman
A M
AM
Lipkowitz
S
S
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
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