The Nedd4-binding partner 1 (N4BP1) protein is an inhibitor of the E3 ligase Itch

Oberst, Andrew; Malatesta, Martina; Aqeilan, Rami I.; Rossi, Mario; Salomoni, Paolo; Murillas, Rodolfo; Sharma, Prashant; Kuehn, Michael R.; Oren, Moshe; Croce, Carlo M.; Bernassola, Francesca; Melino, Gerry

doi:10.1073/pnas.0701773104

Cited by 97 publications

(102 citation statements)

References 29 publications

(33 reference statements)

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“…Data from both our previous and current studies indicate that Wwp2-mediated Lys 63-linked poly-ubiquitination promotes degradation of ectopically as well as endogenously expressed Oct4 through the Ub-proteasome pathway, implying association of Lys 63-linked poly-Ub chains with the proteolytic pathway in mammalian cells. Ub E3 ligases are finely controlled by a variety of mechanisms [38,[41][42][43][44]. Among multiple types of regulation, auto-ubiquitination is known as a means for cells to control the abundance of Ub E3 ligases [38].…”

Section: Discussionmentioning

confidence: 99%

Wwp2 mediates Oct4 ubiquitination and its own auto-ubiquitination in a dosage-dependent manner

Liao

Jin

2009

Cell Res

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Transcription factor Oct4 plays critical roles in maintaining pluripotency and controlling lineage commitment of embryonic stem cells (ESCs). Our previous study indicates that Wwp2, a mouse HECT-type E3 ubiquitin ligase, ubiquitinates Oct4 and promotes its degradation in a heterologous system. However, roles of Wwp2 in regulating endogenous Oct4 protein levels as well as molecular characteristics of the function of Wwp2 have not been determined. Here, we report that Wwp2 plays an important role in Oct4 ubiquitination and degradation during differentiation of embryonal carcinoma cells (ECCs), although it does not appear to affect Oct4 protein levels in the undifferentiated ECCs and ESCs. Importantly, inhibition of Wwp2 expression by specific RNA interference elevates the Oct4 protein level, leading to attenuation in retinoid acid-induced activation of differentiation-related marker genes. Mechanistically, Wwp2 catalyzes Oct4 poly-ubiquitination via the lysine 63 linkage in a dosage-dependent manner. Interestingly, Wwp2 also regulates its own ligase activity in a similar manner. Moreover, auto-ubiquitination of Wwp2 occurs through an intra-molecular mechanism. Taken together, these results demonstrate a crucial role of Wwp2 in controlling endogenous Oct4 protein levels during differentiation processes of ECCs and suggest an interesting dosagedependent mechanism for regulating the catalytic activity of the E3 ubiquitin ligase, Wwp2.

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Section: Discussionmentioning

confidence: 99%

Wwp2 mediates Oct4 ubiquitination and its own auto-ubiquitination in a dosage-dependent manner

Liao

Jin

2009

Cell Res

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“…3C-D). Recently we have also identified a binding patner of Itch able to inhibit its function: N4BP1 [54]. While there is good evidence on how N4BP1 regulates Itch function, there is currently no evidence on its role in the epidemis.…”

Section: Regulation Of Epidermal Keratinocyte Differentiationmentioning

confidence: 99%

p63 in epithelial development

Candi

Cipollone

Cervo

et al. 2008

Cell. Mol. Life Sci.

121

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List of abbreviations: K, keratin; p63-/-, mouse knockout for p63; p63-/-;TA, p63 knockout mice complemented with TAp63; p63-/-;ΔN, p63 knockout mice complemented with ΔNp63; p63-/-;TA;ΔN, p63 knockout mice complemented with both TAp63 and ΔNp63;IKKα, IkB kinase-α; TA, transactivation domain; ΔN, amino-terminal truncated protein. AbstractThe epidermis, the outer layer of the skin composed of keratinocytes, is a stratified epithelium that functions as a barrier to protect the organism from dehydration and external insults. The epidermis develops following the action of the transcription factor p63, a member of the p53 family of transcription factors. The Trp63 gene contains two promoters, driving the production of distinct proteins, one with an N-terminal transactivation domain (TAp63) and one without (DeltaNp63), although their relative contribution to epidermal development is not clearly established. Trp63 mutations are involved in the pathogenesis of several human diseases, phenotypically characterized by ectodermal dysplasia. In this review we summarise the current advances that have been made in understanding the role of p63 in epidermal morphogenesis.

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“…Itch, a group I WW domain protein, and p63 interact with each other through the Itch-WW2 domain and the PPPY sequence (residues 540-543), which is the only PPxY motif in the p63 protein. Although the interaction among the WW2 domain of Itch and the PPxY motif of p63 is crucial for p63 degradation, 87,88 more detailed analysis of this interaction is lacking. This could be of relevance for its potential druggability.…”

Section: -62mentioning

confidence: 99%

p63 threonine phosphorylation signals the interaction with the WW domain of the E3 ligase Itch

et al. 2014

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Both in epithelial development as well as in epithelial cancers, the p53 family member p63 plays a crucial role acting as a master transcriptional regulator. P63 steady state protein levels are regulated by the E3 ubiquitin ligase Itch, via a physical interaction between the PPxY consensus sequence (PY motif) of p63 and one of the 4 WW domains of Itch; this substrate recognition process leads to protein-ubiquitylation and p63 proteasomal degradation. The interaction of the WW domains, a highly compact protein-protein binding module, with the short proline-rich sequences is therefore a crucial regulatory event that may offer innovative potential therapeutic opportunity. Previous molecular studies on the Itch-p63 recognition have been performed in vitro using the Itch-WW2 domain and the peptide interacting fragment of p63 (pep63), which includes the PY motif. Itch-WW2-pep63 interaction is also stabilized in vitro by the conformational constriction of the S-S cyclization in the p63 peptide. The PY motif of p63, as also for other proteins, is characterized by the nearby presence of a (T/S)P motif, which is a potential recognition site of the WW domain of the IV group present in the prolyl-isomerase Pin1. In this study, we demonstrate, by in silico and spectroscopical studies using both the linear pep63 and its cyclic form, that the threonine phosphorylation of the (T/S)PPPxY motif may represent a crucial regulatory event of the Itch-mediated p63 ubiquitylation, increasing the Itch-WW domains-p63 recognition event and stabilizing in vivo the Itch-WW-p63 complex. Moreover, our studies confirm that the subsequently trans/cis proline isomerization of (T/S)P motif by the Pin1 prolyl-isomerase, could modulate the E3-ligase interaction, and that the (T/S) p P trans PPxY motif represent the best conformer for the ItchWW-(T/S)PPPxY motif recognition.

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The Nedd4-binding partner 1 (N4BP1) protein is an inhibitor of the E3 ligase Itch

Cited by 97 publications

References 29 publications

Wwp2 mediates Oct4 ubiquitination and its own auto-ubiquitination in a dosage-dependent manner

Wwp2 mediates Oct4 ubiquitination and its own auto-ubiquitination in a dosage-dependent manner

p63 in epithelial development

p63 threonine phosphorylation signals the interaction with the WW domain of the E3 ligase Itch

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