Identification of multiple proteins expressed in murine embryos as binding partners for the WW domains of the ubiquitin-protein ligase Nedd4

Jolliffe, Corina N.; Harvey, Ken; Haines, Bryan P.; Parasivam, Gayathri; Kumar, Sharad

doi:10.1042/bj3510557

Cited by 84 publications

(59 citation statements)

References 39 publications

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“…Interestingly, SIMPLE has been identified as the binding partner for the WW domain of the ubiquitin-protein ligase NEDD4 and that interaction was shown to depend on the same PPSY motif (Jolliffe et al, 2000). In addition, we demonstrated that WWOX binding to endogenously expressed SIMPLE was dependent on the amino-terminal WWOX WW domain, consistent with our in vitro ligand-binding experiments.…”

Section: Discussionsupporting

confidence: 87%

WWOX binds the specific proline-rich ligand PPXY: identification of candidate interacting proteins

et al. 2004

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WWOX, the gene that maps to common chromosomal fragile site FRA16D, is frequently affected by aberrations in multiple types of cancers. WWOX encodes a 46 kDa protein that contains two WW domains and a short-chain oxidoreductase (SDR) domain. We recently demonstrated that ectopic expression of WWOX inhibits xenograft tumor growth of tumorigenic breast cancer cells. Little is known of the biochemical function(s) of WWOX. The SDR domain is predicted to be involved in sex-steroid metabolism and the WW domains are likely involved in protein-protein interactions. In this report, we identify the specific proline-rich ligand for WWOX as PPXY and show that the amino-terminal WW domain is responsible for this interaction. Using the WWOX WW domains as a probe, we screened high-density protein arrays and identified five candidate-binding partners. The binding to one of these candidates, small membrane protein of the lysosome/late endosome (SIMPLE), was further analysed, and we observed that a specific PPSY motif in the SIMPLE amino-acid sequence was required to interact with the amino-terminal WW domain of WWOX. In addition, immunofluorescence staining demonstrated that endogenous WWOX and SIMPLE co-localize to perinuclear compartments of MCF-7 human breast cancer cells. These studies demonstrate that WWOX contains a Group I WW domain that binds known cellular proteins containing the specific ligand PPXY. Identification and characterization of WWOX interacting proteins will lead to an understanding of the biological functions of WWOX in normal and tumor cells.

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Section: Discussionsupporting

confidence: 87%

WWOX binds the specific proline-rich ligand PPXY: identification of candidate interacting proteins

et al. 2004

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“…The best characterized targets of Nedd4 and its close homologue Nedd4 -2/ KIAA0439 are the epithelial Na ϩ channel (ENaC) subunits, which interact with Nedd4 WW domains via the PY motifs present in the cytosolic carboxyl termini of each subunit (22-28). As the widespread expression of Nedd4 suggests that it may have additional targets, we carried out a far-Western protein expression screen using the WW domains of Nedd4 as a probe and identified eight new Nedd4 WW domain-binding proteins from mouse embryo cDNA libraries (29). Of these, one encoding a novel protein, which we named N4WBP5, was represented in 25% of clones obtained from the screen (29).…”

mentioning

confidence: 99%

N4WBP5, a Potential Target for Ubiquitination by the Nedd4 Family of Proteins, Is a Novel Golgi-associated Protein

Harvey

Shearwin-Whyatt

Fotia

et al. 2002

Journal of Biological Chemistry

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114

130

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Nedd4 belongs to a family of ubiquitin-protein ligases that is characterized by 2-4 WW domains, a carboxylterminal Hect (homologous to E6-AP Carboxyl terminus)-domain and in most cases an amino-terminal C2 domain. We had previously identified a series of proteins that associates with the WW domains of Nedd4. In this paper, we demonstrate that one of the Nedd4-binding proteins, N4WBP5, belongs to a small group of evolutionarily conserved proteins with three transmembrane domains. N4WBP5 binds Nedd4 WW domains via the two PPXY motifs present in the amino terminus of the protein. In addition to Nedd4, N4WBP5 can interact with the WW domains of a number of Nedd4 family members and is ubiquitinated. Endogenous N4WBP5 localizes to the Golgi complex. Ectopic expression of the protein disrupts the structure of the Golgi, suggesting that N4WBP5 forms part of a family of integral Golgi membrane proteins. Based on previous observations in yeast, we propose that N4WBP5 may act as an adaptor for Nedd4-like proteins and their putative targets to control ubiquitin-dependent protein sorting and trafficking.

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“…This site lies within a consensus 14-3-3 binding site (Figure 1). This motif is identical to one found in the HECT-type E3 ligase Nedd4 (Jolliffe et al, 2000), and Nedd4 function has been shown to be regulated by AKT kinase activity (Boehmer et al, 2003). It is known that phosphorylation of a protein within its 14-3-3 binding site can promote interaction with 14-3-3 (i.e.…”

Section: Rnf11 In Tgf-b Signalingmentioning

confidence: 76%

A central role for the ring finger protein RNF11 in ubiquitin-mediated proteolysis via interactions with E2s and E3s

Connor

Seth

2004

Oncogene

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Identification of multiple proteins expressed in murine embryos as binding partners for the WW domains of the ubiquitin-protein ligase Nedd4

Cited by 84 publications

References 39 publications

WWOX binds the specific proline-rich ligand PPXY: identification of candidate interacting proteins

WWOX binds the specific proline-rich ligand PPXY: identification of candidate interacting proteins

N4WBP5, a Potential Target for Ubiquitination by the Nedd4 Family of Proteins, Is a Novel Golgi-associated Protein

A central role for the ring finger protein RNF11 in ubiquitin-mediated proteolysis via interactions with E2s and E3s

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