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PMID:23418353

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Citation

Smith, CJ, Berry, DM and McGlade, CJ (2013) The E3 ubiquitin ligases RNF126 and Rabring7 regulate endosomal sorting of the epidermal growth factor receptor. J. Cell. Sci. 126:1366-80

Abstract

Activation of the epidermal growth factor receptor (EGFR) results in internalization and ubiquitin-dependent endosomal sorting, leading to lysosomal degradation. Here we describe the role of the RING-finger-domain-containing protein RNF126 and the related protein, Rabring7 in EGFR endosomal sorting. We demonstrate that RNF126 specifies K48-linked chains with UbcH5b and also functions with Ubc13/Uev1a to form K63-linked chains in vitro. RNF126 and Rabring7 associate with the EGFR through a ubiquitin-binding zinc finger domain and both E3 ubiquitin ligases promote ubiquitylation of EGFR. In the absence of c-Cbl or in cells expressing Cbl-70Z, the binding of RNF126 and Rabring7 to the EGFR is reduced, suggesting that RNF126 and Rabring7 function downstream of c-Cbl. In HeLa cells depleted of either RNF126 or Rabring7 the EGFR is retained in a late endocytic compartment and is inefficiently degraded. In addition, depletion of RNF126 or Rabring7 destabilizes ESCRT-II and reduces the number of multivesicular bodies formed after EGF stimulation. We also show that the depletion of Rabring7 attenuates the degradation of MET and that both RNF126 and Rabring7 regulate the sorting of CXCR4 from an early endocytic compartment. Together these data suggest that RNF126 and Rabring7 play a role in the ubiquitin-dependent sorting and downregulation of membrane receptors.

Links

PubMed Online version:10.1242/jcs.116129

Keywords

Animals; Endosomes/metabolism; Fibroblasts/metabolism; Gene Knockdown Techniques; Genetic Engineering; HeLa Cells; Humans; Mice; Mutation/genetics; Protein Transport; Proteolysis; Proto-Oncogene Proteins c-cbl/genetics; Proto-Oncogene Proteins c-cbl/metabolism; RNA, Small Interfering/genetics; Receptor, Epidermal Growth Factor/metabolism; Receptors, CXCR4/metabolism; Transgenes/genetics; Ubiquitin-Protein Ligases/genetics; Ubiquitin-Protein Ligases/metabolism; Ubiquitination; fms-Like Tyrosine Kinase 3/genetics; fms-Like Tyrosine Kinase 3/metabolism

Significance

Annotations

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

HUMAN:SCAM3

enables

GO:0031625: ubiquitin protein ligase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q91YL2

F

Seeded From UniProt

complete

MOUSE:FLT3

enables

GO:0031625: ubiquitin protein ligase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q91YL2

F

Seeded From UniProt

complete

HUMAN:CCD50

enables

GO:0031625: ubiquitin protein ligase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q91YL2

F

Seeded From UniProt

complete

MOUSE:RN126

enables

GO:0005154: epidermal growth factor receptor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P00533

F

Seeded From UniProt

complete

MOUSE:RN126

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O14828

F

Seeded From UniProt

complete

MOUSE:RN126

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q00342

F

Seeded From UniProt

complete

MOUSE:RN126

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q8IVM0

F

Seeded From UniProt

complete

MOUSE:RN126

involved_in

GO:0070936: protein K48-linked ubiquitination

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:RN126

involved_in

GO:0070534: protein K63-linked ubiquitination

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:RN126

enables

GO:0061630: ubiquitin protein ligase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:RN126

involved_in

GO:0043162: ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:RN126

involved_in

GO:0042059: negative regulation of epidermal growth factor receptor signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:RN115

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P00533

F

Seeded From UniProt

complete

MOUSE:RN115

involved_in

GO:0070936: protein K48-linked ubiquitination

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:RN115

involved_in

GO:0070534: protein K63-linked ubiquitination

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:RN115

enables

GO:0061630: ubiquitin protein ligase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:RN115

involved_in

GO:0043162: ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:RN115

involved_in

GO:0042059: negative regulation of epidermal growth factor receptor signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:EGFR

enables

GO:0031625: ubiquitin protein ligase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9D0C1

F

Seeded From UniProt

complete

HUMAN:EGFR

enables

GO:0031625: ubiquitin protein ligase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q91YL2

F

Seeded From UniProt

complete

Notes

See also

References

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