cbl-b inhibits EGF-receptor-induced apoptosis by enhancing ubiquitination and degradation of activated receptors.
Studies in C. elegans and Drosophila melanogaster suggest that cbl proteins are inhibitors of epidermal growth factor receptor (EGFR) function. Here we describe that overexpression of cbl-b, a homologue of the c-cbl protooncogene, inhibits EGFR-induced apoptosis in MDA-MB-468 breast cancer cells. Overexpression of cbl-b results in a shortened duration of EGFR activation upon EGF stimulation. This is demonstrated by decreased amounts of phosphorylated EGFR as well as by inhibition of multiple downstream signaling pathways. The inhibition of signaling by cbl-b results from increased ubiquitination and degradation of the activated EGFR. The inhibitory effects of cbl-b overexpression on apoptosis and on EGFR signaling are reversed by blocking proteosomal degradation of the EGFR. These data demonstrate that the mechanism by which cbl-b inhibits EGFR-induced apoptosis is by activation-dependent degradation of the EGFR. They imply that this mechanism may be a general one whereby cbl proteins regulate intracellular signaling.
Ettenberg
S A
SA
Genetics Department, Medicine Branch, National Cancer Institute, National Naval Medical Center, Bethesda, Maryland 20889, USA.
Rubinstein
Y R
YR
Banerjee
P
P
Nau
M M
MM
Keane
M M
MM
Lipkowitz
S
S
D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D048868:Adaptor Proteins, Signal Transducing; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001943:Breast Neoplasms; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000187:drug effects / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000187:drug effects / Q000378:metabolism; D009097:Multienzyme Complexes / Q000187:drug effects / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D050721:Proto-Oncogene Proteins c-cbl; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D044767:Ubiquitin-Protein Ligases; D014452:Ubiquitins / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D015853:Cysteine Proteinase Inhibitors; D009097:Multienzyme Complexes; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D014452:Ubiquitins; C067713:lactacystin; D004815:Epidermal Growth Factor; C492211:CBLB protein, human; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D066246:ErbB Receptors; D020929:Mitogen-Activated Protein Kinase Kinases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D000111:Acetylcysteine