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A mutant EGF‐receptor defective in ubiquitylation and endocytosis unveils a role for Grb2 in negative signaling
Author(s) -
Waterman Hadassa,
Katz Menachem,
Rubin Chanan,
Shtiegman Keren,
Lavi Sara,
Elson Ari,
Jovin Thomas,
Yarden Yosef
Publication year - 2002
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/21.3.303
Subject(s) - biology , grb2 , internalization , ubiquitin ligase , microbiology and biotechnology , ubiquitin , endocytosis , signal transducing adaptor protein , epidermal growth factor receptor , signal transduction , receptor tyrosine kinase , receptor , mutant , biochemistry , gene
Ligand‐induced desensitization of the epidermal growth factor receptor (EGFR) is controlled by c‐Cbl, a ubiquitin ligase that binds multiple signaling proteins, including the Grb2 adaptor. Consistent with a negative role for c‐Cbl, here we report that defective Tyr1045 of EGFR, an inducible c‐Cbl docking site, enhances the mitogenic response to EGF. Signaling potentiation is due to accelerated recycling of the mutant receptor and a concomitant defect in ligand‐induced ubiquitylation and endocytosis of EGFR. Kinetic as well as morphological analyses of the internalization‐defective mutant receptor imply that c‐Cbl‐mediated ubiquitylation sorts EGFR to endocytosis and to subsequent degradation in lysosomes. Unexpectedly, however, the mutant receptor displayed significant residual ligand‐induced ubiquitylation, especially in the presence of an overexpressed c‐Cbl. The underlying mechanism seems to involve recruitment of a Grb2 c‐Cbl complex to Grb2‐specific docking sites of EGFR, and concurrent acceleration of receptor ubiquitylation and desensitization. Thus, in addition to its well‐characterized role in mediating positive signals, Grb2 can terminate signal transduction by accelerating c‐Cbl‐dependent sorting of active tyrosine kinases to destruction.