The Cbl RING finger C-terminal flank controls epidermal growth factor receptor fate downstream of receptor ubiquitination.

Evolutionarily conserved sequences of the E3/protein-ubiquitin ligase Cbl regulate epidermal growth factor receptor (EGF-R) signaling and degradation. These sequences encompass Cbl's tyrosine kinase-binding domain, linker region, RING finger (RF), and an uncharacterized flank C-terminal to the RF (residues 420-436). The latter domain, designated the RF tail, extends beyond Cbl's ubiquitin-conjugating ...
enzyme (Ubc)-binding domain and has no known function. We report structure-function studies evaluating the impact of Cbl RF tail truncations on EGF-R fate in HEK 293 cells. All of the truncation mutants exhibit greatly reduced binding to activated EGF-R and lack proline-rich sequences that mediate direct Cbl association with SH3 proteins such as Grb2, yet a subset of mutants collectively enhances EGF-R ubiquitination, downregulation, and degradation. Significantly, EGF-R degradation correlates better with RF tail-dependent degradation of the Cbl substrate Sprouty2 than with EGF-R ubiquitination: expression of the RF tail truncation mutant Cbl 1-433 enhanced EGF-R ubiquitination while impeding Sprouty2 degradation, and Cbl 1-433 failed to enhance EGF-R downregulation or degradation. Our results suggest that EGF-R fate is controlled by a checkpoint downstream of receptor ubiquitination whose regulation by the Cbl RF tail may require Sprouty2 degradation.
Mesh Terms:
Amino Acid Sequence, Cells, Cultured, Conserved Sequence, Down-Regulation, Evolution, Molecular, Humans, Intracellular Signaling Peptides and Proteins, Molecular Sequence Data, Mutation, Phosphorylation, Protein Structure, Tertiary, Proteins, Proto-Oncogene Proteins c-cbl, Receptor, Epidermal Growth Factor, Sequence Deletion, Tyrosine, Ubiquitin
Exp. Cell Res.
Date: Dec. 10, 2005
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