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PMID:15465819

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Citation

de Melker, AA, van der Horst, G and Borst, J (2004) Ubiquitin ligase activity of c-Cbl guides the epidermal growth factor receptor into clathrin-coated pits by two distinct modes of Eps15 recruitment. J. Biol. Chem. 279:55465-73

Abstract

We have demonstrated previously that c-Cbl requires the presence of a functional ubiquitin interacting motif (UIM) in Eps15 to mediate epidermal growth factor receptor (EGFR) endocytosis. Both the ubiquitin ligase activity of c-Cbl and the UIM of Eps15 were necessary for plasma membrane recruitment of Eps15 and entry of ligand-bound EGFR into coated pits and vesicles containing Eps15. This is consistent with a scenario in which ubiquitin moieties appended to activated EGFR complexes act as docking sites for Eps15 and thereby recruit receptors into clathrin coated pits. Here, we have investigated which additional structural features of c-Cbl are required for this process. We find that c-Cbl can guide ligand-bound EGFR into the Eps15 internalization route by two distinct mechanisms. These are either dependent on the phosphotyrosine binding domain of c-Cbl that directly binds to the EGFR or on the region C-terminal of the Ring finger, which allows for indirect binding to an alternative site on the receptor. No strict requirement exists for either ubiquitin modified EGFR or the Cbl binding ubiquitination substrate CIN85 as docking site for the UIM of Eps15. Only in the phosphotyrosine binding-dependent pathway, the EGFR is ubiquitinated and may serve as a site of recruitment for Eps15. Only in this pathway, Eps15 is tyrosine-phosphorylated, but this appears unrelated to its capacity to participate in EGFR internalization.

Links

PubMed Online version:10.1074/jbc.M409765200

Keywords

Animals; Binding Sites; CHO Cells; COS Cells; Calcium-Binding Proteins/metabolism; Cell Membrane/metabolism; Clathrin-Coated Vesicles/metabolism; Cricetinae; DNA, Complementary/metabolism; Genetic Vectors; Humans; Immunoblotting; Immunoprecipitation; Intracellular Signaling Peptides and Proteins; Ligands; Mice; Microscopy, Fluorescence; Models, Biological; Models, Genetic; Mutation; Phosphoproteins/metabolism; Phosphorylation; Point Mutation; Protein Binding; Protein Structure, Tertiary; Proto-Oncogene Proteins/metabolism; Proto-Oncogene Proteins c-cbl; Receptor, Epidermal Growth Factor/metabolism; Structure-Activity Relationship; Time Factors; Transfection; Tyrosine/chemistry; Ubiquitin/chemistry; Ubiquitin/metabolism; Ubiquitin-Protein Ligases/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:CBL

involved_in

GO:0007173: epidermal growth factor receptor signaling pathway

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CBL

involved_in

GO:0007166: cell surface receptor signaling pathway

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CBL

enables

GO:0004842: ubiquitin-protein transferase activity

ECO:0000304: author statement supported by traceable reference used in manual assertion

F

Seeded From UniProt

complete

HUMAN:CBL

part_of

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:CBL

involved_in

GO:0048260: positive regulation of receptor-mediated endocytosis

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CBL

involved_in

GO:0016567: protein ubiquitination

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:EGFR_original

GO:0005886: plasma membrane

IDA: Inferred from Direct Assay: :

C


HUMAN:EGFR_original

GO:0005886: plasma membrane

IDA: Inferred from Direct Assay:

C


HUMAN:EGFR

part_of

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:EPS15

part_of

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

See also

References

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