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Sci. Signal., 22 December 2009
Vol. 2, Issue 102, p. ra86
[DOI: 10.1126/scisignal.2000217]

RESEARCH ARTICLES

Cbl Controls EGFR Fate by Regulating Early Endosome Fusion

Gina D. Visser Smit1*{dagger}, Trenton L. Place1*, Sara L. Cole2*{dagger}, Kathryn A. Clausen1{dagger}, Soumya Vemuganti1{dagger}, Guojuan Zhang2, John G. Koland1, and Nancy L. Lill2{dagger}{ddagger}

1 Department of Pharmacology, University of Iowa, Iowa City, IA 52242, USA.
2 Department of Pathology and the OSU Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.

* These authors contributed equally to this work.

{dagger} Some results reported here were generated while these authors were affiliated with the University of Iowa.

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.

{ddagger} To whom correspondence should be addressed. E-mail: nancy.lill{at}osumc.edu

Citation: G. D. Visser Smit, T. L. Place, S. L. Cole, K. A. Clausen, S. Vemuganti, G. Zhang, J. G. Koland, N. L. Lill, Cbl Controls EGFR Fate by Regulating Early Endosome Fusion. Sci. Signal. 2, ra86 (2009).

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