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 L. Lill

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

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)
Pages (from-to)ra86
JournalScience signaling
Volume2
Issue number102
DOIs
StatePublished - Dec 22 2009

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'CBL controls EGFR fate by regulating early endosome fusion'. Together they form a unique fingerprint.

Cite this