Cbl controls EGFR fate by regulating early endosome fusion.
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 Val(431)--> Ala mutation, whereas the Cbl- and EGFR-dependent dephosphorylation or degradation of the endosomal trafficking regulator Hrs was compromised by the Phe(434)--> 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.
Visser Smit
Gina D
GD
Department of Pharmacology, University of Iowa, Iowa City, IA 52242, USA.
Place
Trenton L
TL
Cole
Sara L
SL
Clausen
Kathryn A
KA
Vemuganti
Soumya
S
Zhang
Guojuan
G
Koland
John G
JG
Lill
Nancy L
NL
D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D002522:Chlorocebus aethiops; D015536:Down-Regulation / Q000502:physiology*; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D008561:Membrane Fusion / Q000502:physiology*; D008856:Microscopy, Fluorescence; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D056827:Endosomal Sorting Complexes Required for Transport; D010750:Phosphoproteins; C096164:hepatocyte growth factor-regulated tyrosine kinase substrate; D050721:Proto-Oncogene Proteins c-cbl; D066246:ErbB Receptors; C067419:CBL protein, human