Cbl Controls EGFR Fate by Regulating Early Endosome Fusion
- 22 December 2009
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Signaling
- Vol. 2 (102), ra86
- https://doi.org/10.1126/scisignal.2000217
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 EGFR-dependent 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.Keywords
This publication has 31 references indexed in Scilit:
- Ubc4/5 and c-Cbl Continue to Ubiquitinate EGF Receptor after Internalization to Facilitate Polyubiquitination and DegradationMolecular Biology of the Cell, 2008
- EGF and amphiregulin differentially regulate Cbl recruitment to endosomes and EGF receptor fateBiochemical Journal, 2008
- Epidermal Growth Factor Receptor Fate Is Controlled by Hrs Tyrosine Phosphorylation Sites That Regulate Hrs DegradationMolecular and Cellular Biology, 2007
- The Cbl RING finger C-terminal flank controls epidermal growth factor receptor fate downstream of receptor ubiquitinationExperimental Cell Research, 2005
- Growth factors induce differential phosphorylation profiles of the Hrs–STAM complex: a common node in signalling networks with signal-specific propertiesBiochemical Journal, 2005
- CART: An Hrs/Actinin-4/BERP/Myosin V Protein Complex Required for Efficient Receptor RecyclingMolecular Biology of the Cell, 2005
- Tyrosine Phosphorylation of Sprouty Proteins Regulates Their Ability to Inhibit Growth Factor Signaling: A Dual Feedback LoopMolecular Biology of the Cell, 2004
- Cbl-mediated Ubiquitinylation Is Required for Lysosomal Sorting of Epidermal Growth Factor Receptor but Is Dispensable for EndocytosisJournal of Biological Chemistry, 2003
- Hrs regulates early endosome fusion by inhibiting formation of an endosomal SNARE complexThe Journal of cell biology, 2003
- Evidence for Direct Interaction between Sprouty and CblPublished by Elsevier BV ,2001