CBL controls EGFR fate by regulating early endosome fusion

Gina D. Visser Smit, Trenton L. Place, Sara L. Cole, Kathryn A. Clausen, Soumya Vemugantl, Guojuan Zhang, John G. Koland, Nancy Lill

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Amino acid residues 1 to 434 of the E3 ubiquitin ligase Cbl control signaling of the epidermal growth factor receptor (EGFR) by enhancing its ubiquitination, down-regulation, and lysosomal degradation. This region of Cbl comprises a tyrosine kinase-binding domain, a linker region, a really interesting new gene finger (RF), and a subset of the residues of the RF tail. In experiments with full-length alanine substitution mutants, we demonstrated that the RF tail of Cbl regulated biochemically distinct checkpoints in the endocytosis of EGFR. The Cbl- and ubiquitin-dependent degradation of the regulator of internalization hSprouty2 was compromised by the Val431→ Ala mutation, whereas the Cbl- and EGFRdependent dephosphorylation or degradation of the endosomal trafficking regulator Hrs was compromised by the Phe434? Ala mutation. Deregulated phosphorylation of Hrs correlated with inhibition of the fusion of early endosomes and of the degradation of EGFR. This study provides the first evidence that Cbl regulates receptor fate by controlling the fusion of sorting endosomes. We postulate that it does so by modulating the abundance of tyrosine-phosphorylated Hrs.

Original languageEnglish (US)
JournalScience Signaling
Volume2
Issue number102
DOIs
StatePublished - Dec 22 2009

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Endosomes
Epidermal Growth Factor Receptor
Fusion reactions
Degradation
Mutation
Ubiquitin-Protein Ligases
Ubiquitination
Ubiquitin
Endocytosis
Alanine
Protein-Tyrosine Kinases
Phosphorylation
Fingers
Tyrosine
Down-Regulation
Sorting
Amino Acids
Substitution reactions
Genes
Experiments

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Visser Smit, G. D., Place, T. L., Cole, S. L., Clausen, K. A., Vemugantl, S., Zhang, G., ... Lill, N. (2009). CBL controls EGFR fate by regulating early endosome fusion. Science Signaling, 2(102). https://doi.org/10.1126/scisignal.2000217
Visser Smit, Gina D. ; Place, Trenton L. ; Cole, Sara L. ; Clausen, Kathryn A. ; Vemugantl, Soumya ; Zhang, Guojuan ; Koland, John G. ; Lill, Nancy. / CBL controls EGFR fate by regulating early endosome fusion. In: Science Signaling. 2009 ; Vol. 2, No. 102.
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Visser Smit, GD, Place, TL, Cole, SL, Clausen, KA, Vemugantl, S, Zhang, G, Koland, JG & Lill, N 2009, 'CBL controls EGFR fate by regulating early endosome fusion', Science Signaling, vol. 2, no. 102. https://doi.org/10.1126/scisignal.2000217

CBL controls EGFR fate by regulating early endosome fusion. / Visser Smit, Gina D.; Place, Trenton L.; Cole, Sara L.; Clausen, Kathryn A.; Vemugantl, Soumya; Zhang, Guojuan; Koland, John G.; Lill, Nancy.

In: Science Signaling, Vol. 2, No. 102, 22.12.2009.

Research output: Contribution to journalArticle

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Visser Smit GD, Place TL, Cole SL, Clausen KA, Vemugantl S, Zhang G et al. CBL controls EGFR fate by regulating early endosome fusion. Science Signaling. 2009 Dec 22;2(102). https://doi.org/10.1126/scisignal.2000217