HECT Domain-containing E3 Ubiquitin Ligase NEDD4L Negatively Regulates Wnt Signaling by Targeting Dishevelled for Proteasomal Degradation

Ding, Yi; Zhang, Yan; Xu, Chao; Tao, Qinghua; Chen, Ye-Guang

doi:10.1074/jbc.m112.433185

Cited by 107 publications

(109 citation statements)

References 46 publications

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“…In accordance with these findings, two other studies further demonstrated NEDD4L's suppression of Wnt signaling to be mediated by Dishevelled-2 (Dvl2), a pivotal transducer of Wnt signals [61,72]. After Wnt proteins/ligands bind to their receptors, the signal is transduced to Dishevelled phosphoproteins, a crucial node where Wnt signaling diverges into at least three major cascades: canonical (Wnt/β-catenin), Planar Cell Polarity (PCP) and Wnt/Ca 2+ [73].…”

Section: Nedd4l (Nedd4-2)supporting

confidence: 50%

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Molecular functions of NEDD4 E3 ubiquitin ligases in cancer

Zou

Levy-Cohen

Blank

2015

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

106

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Section: Nedd4l (Nedd4-2)supporting

confidence: 50%

“…NEDD4L has been implicated in the regulation of a number of central pathways in cancer, including TGF-β [59,60], Wnt [61,62] and EGFR [63] signaling pathways. NEDD4L negatively regulates TGF-β/BMP signaling by inducing ubiquitination-mediated degradation of TGF-β type I receptor (TGF-R1) and receptor-regulated Smad2 [59].…”

Section: Nedd4l (Nedd4-2)mentioning

confidence: 99%

Molecular functions of NEDD4 E3 ubiquitin ligases in cancer

Zou

Levy-Cohen

Blank

2015

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

106

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“…It is well established that the stereotyped branching program is dependent on precise cross-talk among multiple signaling pathways, including SHH, FGF, WNT, BMP, and TGF-β (1, 2). A number of E3 ubiquitin ligases have been identified to regulate substrates within these signaling pathways, such as ITCH (targets protein patched homolog 1, SHH pathway), vHL [targets protein sprouty homolog 2 (SPRY2), FGF pathway], NEDD4 (targets fibroblast growth factor receptor 1, FGF pathway), RNF43 (targets transcription factor 4, canonical WNT pathway), NEDD4L (targets segment polarity protein dishevelled homolog DVL-2, canonical WNT pathway), TRIM36 (unknown, targets noncanonical WNT pathway), and SMURF1 and SMURF2 (target SMADs, TGF-β/BMP pathway) (5,38,39,(48)(49)(50)(51)(52). These factors may function together with RFWD2 to ensure order at the protein level during the construction of a functional lung.…”

Section: Discussionmentioning

confidence: 99%

E3 ubiquitin ligase RFWD2 controls lung branching through protein-level regulation of ETV transcription factors

Zhang

Yokoyama

Herriges

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The mammalian lung is an elaborate branching organ, and it forms following a highly stereotypical morphogenesis program. It is well established that precise control at the transcript level is a key genetic underpinning of lung branching. In comparison, little is known about how regulation at the protein level may play a role. Ring finger and WD domain 2 (RFWD2, also termed COP1) is an E3 ubiquitin ligase that modifies specific target proteins, priming their degradation via the ubiquitin proteasome system. RFWD2 is known to function in the adult in pathogenic processes such as tumorigenesis. Here, we show that prenatal inactivation of Rfwd2 gene in the lung epithelium led to a striking halt in branching morphogenesis shortly after secondary branch formation. This defect is accompanied by distalization of the lung epithelium while growth and cellular differentiation still occurred. In the mutant lung, two E26 transformation-specific (ETS) transcription factors essential for normal lung branching, ETS translocation variant 4 (ETV4) and ETV5, were up-regulated at the protein level, but not at the transcript level. Introduction of Etv loss-of-function alleles into the Rfwd2 mutant background attenuated the branching phenotype, suggesting that RFWD2 functions, at least in part, through degrading ETV proteins. Because a number of E3 ligases are known to target factors important for lung development, our findings provide a preview of protein-level regulatory network essential for lung branching morphogenesis.T he vital role of the mammalian lung as a gas-exchange organ is built on the basis of a remarkably elaborate branching sequence during lung development. In the mouse, lung development initiates at embryonic day (E) 9.5 with the formation of two primary lung buds (1, 2). Subsequently, these lung buds elongate and undergo multiple rounds of branching, following a largely stereotyped routine (3, 4). Extensive feedback regulations at the level of transcription have been shown to play central roles in branching (1, 2). In comparison, little is known on how control at the protein level is required for the process in vivo. One study showed that overexpression of SMAD specific ubiquitin protein ligase 1 (Smurf1) led to down-regulation of SMAD family members and a branching defect in lung explant culture (5).The ubiquitin proteasome system is a fundamental molecular mechanism that controls protein homeostasis. Selective degradation of protein substrates by this system involves sequential function of three classes of enzymes: ubiquitin-activating enzyme E1, ubiquitinconjugating enzyme E2, and ubiquitin-protein ligase E3 (6, 7). In a mammalian organism such as the mouse, although there are only a handful of E1 and E2 enzymes that act in the core pathway to mark all protein substrates, there are several hundred E3 ubiquitin ligases, each with a small set of substrates, thus providing specificity (8).E3 ubiquitin ligase Ring finger and WD domain 2 (RFWD2, also known as COP1) was first identified as a regulator in the light sign...

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“…We next tested it in an assay for the ubiquitination and degradation of the Dishevelled protein (Dvl). Dvl contains a PY motif and is a substrate for several members of the Nedd4 family (22)(23)(24)(25), which bind PY motifs via their WW domains. This was readily demonstrated by coexpression of Dvl2 with Smurf2 and other ligases.…”

Section: Significancementioning

confidence: 99%

Peptide and small molecule inhibitors of HECT-type ubiquitin ligases

Mund

Lewis

Maslen

2014

Proc. Natl. Acad. Sci. U.S.A.

129

133

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The human genome encodes several hundred E3 ubiquitin ligases containing RING domains, and around 28 containing HECT domains. These enzymes catalyze the transfer of ubiquitin from E2 enzyme thioesters to a huge range of substrates and play crucial roles in many cellular functions. This makes them attractive potential therapeutic targets. However, they have proven difficult to inhibit: very few good inhibitors exist for RING domain ligases, and none have been described for HECT ligases. Here we show that bicyclic peptides isolated by phage display [Heinis C, Rutherford T, Freund S, Winter G (2009) Nat Chem Biol. 5(7):502-507] can target the E2 binding sites on the HECT domains of Smurf2, Nedd4, Mule/ Huwe1, and WWP1, and thus act as specific inhibitors of these enzymes in vitro. By screening for displacement of one of these peptides from Smurf2, we were able to identify a small molecule, heclin (HECT ligase inhibitor), which inhibits several HECT ligases in tissue culture cells. In vitro, heclin does not block E2 binding but causes a conformational change that results in oxidation of the active site Cys. This demonstrates that HECT domains are potentially druggable and provides molecules that may be of experimental use. Heclin kills HEK293 cells growing in culture, consistent with an essential role for HECT ligase activity in mammalian cells.inhibitor | ubiquitin | HECT ligase | phage display U biquitin ligases are involved in almost every important function of cells, including the removal of misfolded proteins, the regulation of signaling pathways, DNA repair, the cell cycle, and apoptosis (1-4). This broad range of functions is mediated by a large number of E3 ubiquitin ligases, which recognize a similarly large range of substrates. Ubiquitination begins with the ATP-dependent formation of a ubiquitin (Ub)-E2 enzyme thioester intermediate by the E1 enzyme. The E3 enzymes then transfer ubiquitin from this intermediate to a lysine residue on the substrate (3). There are two main classes of E3: the RING domain ligases and their relatives, of which there are several hundred in humans, and the HECT domain ligases, which number around 28 (5-7). Because of their diversity and numerous functions and the fact that some ligases are frequently overexpressed in cancer cells, ubiquitin ligases have attracted much attention as possible targets for therapeutic intervention (2,5,6,8).Despite this interest, it has proven challenging to make small molecule inhibitors of ubiquitin ligases. The action of these enzymes involves primarily protein-protein interactions among them, the Ub-E2 conjugate, and the substrate. For the RING enzymes, this is simultaneous, and the Ub moiety is transferred directly from E2 to substrate; for the HECT ligases, the interaction is sequential, with a thioester-linked Ub-E3 intermediate forming transiently. Such protein-protein interactions are considered difficult to block with small molecules. Added to this difficulty has been the complexity of the ubiquitin system, with ligases having many substrat...

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HECT Domain-containing E3 Ubiquitin Ligase NEDD4L Negatively Regulates Wnt Signaling by Targeting Dishevelled for Proteasomal Degradation

Cited by 107 publications

References 46 publications

Molecular functions of NEDD4 E3 ubiquitin ligases in cancer

Molecular functions of NEDD4 E3 ubiquitin ligases in cancer

E3 ubiquitin ligase RFWD2 controls lung branching through protein-level regulation of ETV transcription factors

Peptide and small molecule inhibitors of HECT-type ubiquitin ligases

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