Research ArticleEndocytosis

Cbl Controls EGFR Fate by Regulating Early Endosome Fusion

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Science Signaling  22 Dec 2009:
Vol. 2, Issue 102, pp. ra86
DOI: 10.1126/scisignal.2000217

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Cbl and Endosomes

The E3 ubiquitin ligase Cbl causes the mono- and polyubiquitination of receptor tyrosine kinases (RTKs), such as the epidermal growth factor receptor (EGFR), thereby targeting these proteins for degradation in lysosomes. RTK trafficking also depends on the modification of other Cbl-associated proteins at the plasma membrane and in endosomes, but how these work together to control RTK trafficking is not well understood. Critical to the ubiquitination function of Cbl is the really interesting new gene (RING) finger (RF) tail region, which prompted Visser Smit et al. to investigate the effects of single substitution mutants in this region of Cbl on the ubiquitination, down-regulation, and degradation of EGFR. They found that individual amino acid residues in the RF tail contributed differently to these processes and that Cbl played a role in EGFR internalization independently of its ability to ubiquitinate the receptor. In particular, Cbl was required for the fusion of early endosomes that trafficked EGFR to lysosomes, which depended, in part, on Hrs, a regulator of EGFR trafficking. Given the role of Cbl in mediating the down-regulation of multiple RTKs, its ability to control endosomal maturation may have general implications for controlling RTK activity.