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PMID:17592138

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Citation

Oberst, A, Malatesta, M, Aqeilan, RI, Rossi, M, Salomoni, P, Murillas, R, Sharma, P, Kuehn, MR, Oren, M, Croce, CM, Bernassola, F and Melino, G (2007) The Nedd4-binding partner 1 (N4BP1) protein is an inhibitor of the E3 ligase Itch. Proc. Natl. Acad. Sci. U.S.A. 104:11280-5

Abstract

Nedd4-binding partner-1 (N4BP1) has been identified as a protein interactor and a substrate of the homologous to E6AP C terminus (HECT) domain-containing E3 ubiquitin-protein ligase (E3), Nedd4. Here, we describe a previously unrecognized functional interaction between N4BP1 and Itch, a Nedd4 structurally related E3, which contains four WW domains, conferring substrate-binding activity. We show that N4BP1 association with the second WW domain (WW2) of Itch interferes with E3 binding to its substrates. In particular, we found that N4BP1 and p73 alpha, a target of Itch-mediated ubiquitin/proteasome proteolysis, share the same binding site. By competing with p73 alpha for binding to the WW2 domain, N4BP1 reduces the ability of Itch to recruit and ubiquitylate p73 alpha and inhibits Itch autoubiquitylation activity both in in vitro and in vivo ubiquitylation assays. Similarly, both c-Jun and p63 polyubiquitylation by Itch are inhibited by N4BP1. As a consequence, genetic and RNAi knockdown of N4BP1 diminish the steady-state protein levels and significantly impair the transcriptional activity of Itch substrates. Notably, stress-induced induction of c-Jun was impaired in N4BP1(-/-) cells. These results demonstrate that N4BP1 functions as a negative regulator of Itch. In addition, because inhibition of Itch by N4BP1 results in the stabilization of crucial cell death regulators such as p73 alpha and c-Jun, it is conceivable that N4BP1 may have a role in regulating tumor progression and the response of cancer cells to chemotherapy.

Links

PubMed PMC2040890 Online version:10.1073/pnas.0701773104

Keywords

Animals; Apoptosis/physiology; Carrier Proteins/metabolism; Carrier Proteins/physiology; Cells, Cultured; DNA-Binding Proteins/metabolism; DNA-Binding Proteins/physiology; Endosomal Sorting Complexes Required for Transport; Enzyme Inhibitors/chemistry; Enzyme Inhibitors/metabolism; Membrane Proteins/metabolism; Mice; Mice, Knockout; Nuclear Proteins/metabolism; Nuclear Proteins/physiology; Protein Binding/physiology; Protein Structure, Tertiary/physiology; Proto-Oncogene Proteins c-jun/genetics; Proto-Oncogene Proteins c-jun/metabolism; Substrate Specificity/genetics; Substrate Specificity/physiology; Tumor Suppressor Proteins/metabolism; Tumor Suppressor Proteins/physiology; Ubiquitin-Protein Ligases/antagonists & inhibitors; Ubiquitin-Protein Ligases/metabolism; Ubiquitin-Protein Ligases/physiology

Significance

Annotations

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

HUMAN:P73

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q96J02

F

Seeded From UniProt

complete

HUMAN:N4BP1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q96J02

F

Seeded From UniProt

complete

HUMAN:N4BP1

involved_in

GO:0034644: cellular response to UV

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:N4BP1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q96J02

F

Seeded From UniProt

complete

MOUSE:N4BP1

involved_in

GO:0032435: negative regulation of proteasomal ubiquitin-dependent protein catabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:N4BP1

involved_in

GO:0031397: negative regulation of protein ubiquitination

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:N4BP1

involved_in

GO:0034644: cellular response to UV

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ITCH

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q6A037

F

Seeded From UniProt

complete

HUMAN:ITCH

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O15350

F

Seeded From UniProt

complete

HUMAN:ITCH

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O75113

F

Seeded From UniProt

complete

HUMAN:ITCH

involved_in

GO:0016567: protein ubiquitination

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ITCH

enables

GO:0004842: ubiquitin-protein transferase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete


See also

References

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