Ubiquitin ligase activity and tyrosine phosphorylation underlie suppression of growth factor signaling by c-Cbl/Sli-1.
Receptor desensitization is accomplished by accelerated endocytosis and degradation of ligand-receptor complexes. An in vitro reconstituted system indicates that Cbl adaptor proteins directly control downregulation of the receptor for the epidermal growth factor (EGFR) by recruiting ubiquitin-activating and -conjugating enzymes. We infer a sequential process initiated by autophosphorylation of EGFR at a previously identified lysosome-targeting motif that subsequently recruits Cbl. This is followed by tyrosine phosphorylation of c-Cbl at a site flanking its RING finger, which enables receptor ubiquitination and degradation. Whereas all three members of the Cbl family can enhance ubiquitination, two oncogenic Cbl variants, whose RING fingers are defective and phosphorylation sites are missing, are unable to desensitize EGFR. Our study identifies Cbl proteins as components of the ubiquitin ligation machinery and implies that they similarly suppress many other signaling pathways.
Levkowitz
G
G
Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
Waterman
H
H
Ettenberg
S A
SA
Katz
M
M
Tsygankov
A Y
AY
Alroy
I
I
Lavi
S
S
Iwai
K
K
Reiss
Y
Y
Ciechanover
A
A
Lipkowitz
S
S
Yarden
Y
Y
D029742:Caenorhabditis elegans Proteins; D002474:Cell-Free System; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000502:physiology*; D066246:ErbB Receptors / Q000502:physiology*; D015801:Helminth Proteins / Q000502:physiology*; D008025:Ligases / Q000502:physiology*; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D050721:Proto-Oncogene Proteins c-cbl; D015398:Signal Transduction; D014443:Tyrosine; D044764:Ubiquitin-Activating Enzymes; D044767:Ubiquitin-Protein Ligases
D029742:Caenorhabditis elegans Proteins; D015801:Helminth Proteins; D011518:Proto-Oncogene Proteins; C095237:Sli-1 protein, C elegans; D014443:Tyrosine; D004815:Epidermal Growth Factor; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D066246:ErbB Receptors; D008025:Ligases; D044764:Ubiquitin-Activating Enzymes