Molecular mechanisms of coupled monoubiquitination

Woelk, Tanja; Oldrini, Barbara; Maspero, Elena; Confalonieri, Stefano; Cavallaro, Elena; Fiore, Pier Paolo Di; Polo, Simona

doi:10.1038/ncb1484

Cited by 170 publications

(197 citation statements)

References 39 publications

Supporting

Mentioning

190

Contrasting

Order By: Relevance

“…It is well established that the abnormal activation of the EGF receptors is a common theme in epithelial cancer (Yarden, 2001). Nedd4 and Itch have been demonstrated to inhibit EGFR degradation through ubiquitinating multiple adaptor proteins essential for endocytosis such as Cbls (Courbard et al, 2002;Magnifico et al, 2003), EPS15 (Woelk et al, 2006), Hgs (Katz et al, 2002) or Endophilin A1 (Angers et al, 2004). However, whether WWP1 also regulates EGFRs has never been explored.…”

Section: Introductionmentioning

confidence: 99%

“…EPS15 and Cbl have been demonstrated to be RNF11-interacting proteins in yeast two-hybrid experiments (Azmi and Seth, 2005). WWP1 has been shown to increase the ubiquitination of EPS15 (Woelk et al, 2006;Chen and Matesic, 2007). In addition, a WWP1 family member, Itch/AIP4, has been shown to promote Cbl ubiquitination (Magnifico et al, 2003).…”

Section: Wwp1 Upregulates Erbb2 and Egfr Through Rnf11mentioning

confidence: 99%

See 1 more Smart Citation

The WW domain containing E3 ubiquitin protein ligase 1 upregulates ErbB2 and EGFR through RING finger protein 11

et al. 2008

View full text Add to dashboard Cite

The WW domain containing E3 ubiquitin protein ligase 1 (WWP1) is a homologous to the E6-associated protein C terminus-type E3 ligase frequently overexpressed in human prostate and breast cancers due to gene amplification. Previous studies suggest that WWP1 promotes cell proliferation and survival; however, the mechanism of WWP1 action is still poorly understood. Here, we showed that WWP1 upregulates and maintains erythroblastic leukemia viral oncogene homolog 2 (ErbB2) and epithelial growth factor receptor (EGFR) in multiple cell lines. WWP1 depletion dramatically attenuates the EGFinduced ERK phosphorylation. WWP1 forms a protein complex with RING finger protein 11 (RNF11), a negative regulator of ErbB2 and EGFR. The proteinprotein interaction is through the first and third WW domains of WWP1 and the PY motif of RNF11. Although WWP1 is able to ubiquitinate RNF11 in vitro and in vivo, WWP1 neither targets RNF11 for degradation nor changes RNF11's cellular localization. Importantly, inhibition of RNF11 can rescue WWP1 siRNA-induced ErbB2 and EGFR downregulation and growth arrest. Finally, we demonstrated that RNF11 is overexpressed in a panel of prostate and breast cancer cell lines with WWP1 expression. These findings suggest that WWP1 may promote cell proliferation and survival partially through suppressing RNF11-mediated ErbB2 and EGFR downregulation.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Wwp1 Upregulates Erbb2 and Egfr Through Rnf11mentioning

confidence: 99%

The WW domain containing E3 ubiquitin protein ligase 1 upregulates ErbB2 and EGFR through RING finger protein 11

et al. 2008

View full text Add to dashboard Cite

show abstract

“…70,71 Another example for self-ubiquitination-dependent recruitment of substrates was reported for NEDD4: its self-catalyzed monoubiquitination serves to recruit EPS15, which is subsequently also monoubiquitinated by NEDD4. 72 The function of monoubiquitination of EPS15 still remains an enigma, but it might have an inhibitory role in the function of EPS15 to facilitate clathrin-mediated endocytosis of transmembrane proteins. 73 …”

Section: Non-proteolytic Functions Of Self-ubiquitination Of E3smentioning

confidence: 99%

Ubiquitination of E3 ligases: self-regulation of the ubiquitin system via proteolytic and non-proteolytic mechanisms

2011

View full text Add to dashboard Cite

Ubiquitin modification of many cellular proteins targets them for proteasomal degradation, but in addition can also serve non-proteolytic functions. Over the last years, a significant progress has been made in our understanding of how modification of the substrates of the ubiquitin system is regulated. However, little is known on how the ubiquitin system that is comprised of B1500 components is regulated. Here, we discuss how the biggest subfamily within the system, that of the E3 ubiquitin ligases that endow the system with its high specificity towards the numerous substrates, is regulated and in particular via self-regulation mediated by ubiquitin modification. Ligases can be targeted for degradation in a self-catalyzed manner, or through modification mediated by an external ligase(s). In addition, non-proteolytic functions of self-ubiquitination, for example activation of the ligase, of E3s are discussed. Cell Death and Differentiation (2011) 18, 1393-1402 doi:10.1038/cdd.2011; published online 4 March 2011One of the major roles of the covalent modification of cellular proteins by ubiquitin is signaling them for proteasomal degradation ( Figure 1). The first step of the modification is catalyzed by the ubiquitin-activating enzyme, E1, which generates a high-energy thiol ester intermediate that is subsequently transferred to the second enzyme, a ubiquitinconjugating enzyme, E2. The third step ascertains substrate specificity, and is catalyzed by one of the numerous (B650) ubiquitin ligases, E3s. Typically, it results in the formation of an isopeptide bond between the C-terminal Gly of ubiquitin and an e-NH 2 group of an internal Lys of the substrate. Less frequently, it can generate a linear peptide bond with the a-NH 2 group, a thiol ester bond with an internal Cys, or an ester bond with a Thr or Ser. The three-step cascade of reactions is repeated, where additional ubiquitin moieties are attached sequentially to one another in an isopeptide bond involving one of the seven internal Lys residues in the ubiquitin moiety, thus generating a polyubiquitin chain. Lys48-based chains serve as a signal for proteasomal degradation, whereas chains based on other internal Lys residues, or modification by single moiety(ies) can serve non-proteolytic functions.Ligases fall into two main families: RING (really interesting new gene) and HECT (homologous to the E6-AP carboxy terminus) domain-containing E3s. RING ligases serve as scaffolds that facilitate direct transfer of ubiquitin from the E2 to the target protein. HECT E3s contain an active Cys residue to which ubiquitin binds prior to its transfer to the substrate (Figure 1). There are B600 RING finger and B30 HECT ligases in humans. Smaller families of ligases (U-box, plant homology domain, and zinc finger) have also been described.An important problem relates to regulation of the ubiquitin system components, and in particular to that of the ligases that are the specific substrate-recognizing elements. 1,2 Phosphorylation of an E3 can activate the protein, such as the ca...

show abstract

“…Recent research has shown that ubiquitination not only leads the protein substrate to the proteasome or lysosome for degradation, but also regulates various cellular functions, including signal transduction, endocytic trafficking and DNA repair without affecting protein stability [31]. Many proteins contain ubiquitinbinding domains or motifs that function as ubiquitin receptors for protein-protein interactions [32]. It is thus intriguing to determine whether such a mechanism is involved in regulating mitochondrial dynamics.…”

Section: Introductionmentioning

confidence: 99%

A small natural molecule promotes mitochondrial fusion through inhibition of the deubiquitinase USP30

et al. 2014

View full text Add to dashboard Cite

Mitochondrial fusion is a highly coordinated process that mixes and unifies the mitochondrial compartment for normal mitochondrial functions and mitochondrial DNA inheritance. Dysregulated mitochondrial fusion causes mitochondrial fragmentation, abnormal mitochondrial physiology and inheritance, and has been causally linked with a number of neuronal diseases. Here, we identified a diterpenoid derivative 15-oxospiramilactone (S3) that potently induced mitochondrial fusion to restore the mitochondrial network and oxidative respiration in cells that are deficient in either Mfn1 or Mfn2. A mitochondria-localized deubiquitinase USP30 is a target of S3. The inhibition of USP30 by S3 leads to an increase of non-degradative ubiquitination of Mfn1/2, which enhances Mfn1 and Mfn2 activity and promotes mitochondrial fusion. Thus, through the use of an inhibitor of USP30, our study uncovers an unconventional function of non-degradative ubiquitination of Mfns in promoting mitochondrial fusion.

show abstract

Molecular mechanisms of coupled monoubiquitination

Cited by 170 publications

References 39 publications

The WW domain containing E3 ubiquitin protein ligase 1 upregulates ErbB2 and EGFR through RING finger protein 11

The WW domain containing E3 ubiquitin protein ligase 1 upregulates ErbB2 and EGFR through RING finger protein 11

Ubiquitination of E3 ligases: self-regulation of the ubiquitin system via proteolytic and non-proteolytic mechanisms

A small natural molecule promotes mitochondrial fusion through inhibition of the deubiquitinase USP30

Contact Info

Product

Resources

About