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  • The EMBO Journal (2002) 21, 303 - 313
  • doi:10.1093/emboj/21.3.303



There is a Corrigendum (July 2002) associated with this Article.

A mutant EGF-receptor defective in ubiquitylation and endocytosis unveils a role for Grb2 in negative signaling

Hadassa Waterman1, Menachem Katz1, Chanan Rubin1, Keren Shtiegman1, Sara Lavi1, Ari Elson2, Thomas Jovin3 and Yosef Yarden1

  1. Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel
  2. Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel
  3. Department of Molecular Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, D-37077 Gottingen, Germany

Correspondence to:

Yosef Yarden, E-mail: yosef.yarden@weizmann.ac.il

Received 24 May 2001; Accepted 23 November 2001; Revised 31 October 2001

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.

  • Keywords:

    • growth factor,
    • SH2 domain,
    • signal transduction,
    • tyrosine kinase,
    • ubiquitin ligase