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PMID:14755250

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Citation

Li, H and Seth, A (2004) An RNF11: Smurf2 complex mediates ubiquitination of the AMSH protein. Oncogene 23:1801-8

Abstract

RING-finger proteins play crucial roles in ubiquitination events involved in diverse cellular processes including signal transduction, differentiation and apoptosis. Most of the RING-finger proteins have E3-ubiquitin ligase activity. RNF11 is a small RING-finger protein and harbors a RING-H2 domain and a PY motif that could facilitate protein:protein interaction(s) involved in oncogenesis. To isolate RNF11 protein partners and determine its role in normal and cancer cells, we performed yeast two-hybrid screening. Among 18 in-frame positive clones, three were found to be ZBRK1, Eps15 and AMSH (associated molecule with the SH3 domain of STAM). ZBRK1 is a KRAB domain containing Zinc-finger protein and is known to repress target gene transcription in a BRCA1-dependent manner. Eps15 is monoubiquitinated and is part of an essential complex involved in the endocytosis of plasma membrane receptors via the clathrin-mediated internalization pathway. Recent studies have shown that AMSH protein is involved in BMP/TGF-beta signaling pathway by binding to Smad6 and Smad7. The association of RNF11 with these binding partners suggests that it would be involved in biological processes such as gene transcription, BMP/TGF-beta signaling and ubiquitination-associated events. Previously, we have shown that RNF11 interacts with the HECT-type E3 ligases AIP4 and Smurf2. Here, we show that RNF11 binds to AMSH in mammalian cells and that this interaction is independent of the RNF11 RING-finger domain and the PY motif. Our results also demonstrate that AMSH is ubiquitinated by Smurf2 E3 ligase in the presence of RNF11 and that a consequent reduction in its steady-state level requires both RNF11 and Smurf2. RNF11 therefore recruits AMSH to Smurf2 for ubiquitination, leading to its degradation by the 26S proteasome. The potential functions of RNF11-mediated degradation of AMSH in breast cancer are discussed.

Links

PubMed Online version:10.1038/sj.onc.1207319

Keywords

Amino Acid Substitution; Binding Sites; Carrier Proteins/genetics; Carrier Proteins/metabolism; Cell Line; Cloning, Molecular; Endopeptidases; Endosomal Sorting Complexes Required for Transport; Genes, Reporter; Humans; Luciferases/genetics; Mutagenesis, Insertional; Mutagenesis, Site-Directed; Saccharomyces cerevisiae/genetics; Saccharomyces cerevisiae/metabolism; Transfection; Ubiquitin/metabolism; Ubiquitin Thiolesterase; Ubiquitin-Protein Ligases/genetics; Ubiquitin-Protein Ligases/metabolism; Zinc Fingers/genetics; src Homology Domains

Significance

Annotations

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

HUMAN:STABP

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P0CG47

F

Seeded From UniProt

complete

HUMAN:STABP

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9Y3C5

F

Seeded From UniProt

complete

HUMAN:UBB

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O95630

F

Seeded From UniProt

complete

HUMAN:UBB

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9HAU4

F

Seeded From UniProt

complete

HUMAN:UBB

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9Y3C5

F

Seeded From UniProt

complete

HUMAN:RS27A

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9Y3C5

F

Seeded From UniProt

complete

HUMAN:SMUF2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P0CG47

F

Seeded From UniProt

complete

HUMAN:SMUF2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9Y3C5

F

Seeded From UniProt

complete

HUMAN:RNF11

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O95630

F

Seeded From UniProt

complete

HUMAN:RNF11

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P0CG47

F

Seeded From UniProt

complete

HUMAN:RNF11

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P62979

F

Seeded From UniProt

complete

HUMAN:RNF11

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9HAU4

F

Seeded From UniProt

complete

HUMAN:RNF11

involved_in

GO:0006511: ubiquitin-dependent protein catabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:RNF11

part_of

GO:0000151: ubiquitin ligase complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:SMUF2

part_of

GO:0000151: ubiquitin ligase complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:SMUF2

enables

GO:0004842: ubiquitin-protein transferase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:SMUF2

involved_in

GO:0006511: ubiquitin-dependent protein catabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

See also

References

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