Ubiquitin ligase activity and tyrosine phosphorylation underlie suppression of growth factor signaling by c-Cbl/Sli-1

Gil Levkowitz, Hadassa Waterman, Seth A. Ettenberg, Menachem Katz, Alexander Y. Tsygankov, Iris Alroy, Sara Lavi, Kazuhiro Iwai, Yuval Reiss, Aaron Ciechanover, Stanley Lipkowitz, Yosef Yarden*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1029-1040
Number of pages12
JournalMolecular Cell
Volume4
Issue number6
DOIs
StatePublished - Dec 1999
Externally publishedYes

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