Regulation of Planar Cell Polarity by Smurf Ubiquitin Ligases

Narimatsu, Masahiro; Bose, Rohit; Pye, Melanie; Zhang, Liang; Miller, Bryan W.; Ching, Peter; Sakuma, Rui; Luga, Valbona; Roncari, Luba; Attisano, Liliana; Wrana, Jeffrey L.

doi:10.1016/j.cell.2009.02.025

Cited by 303 publications

(354 citation statements)

References 46 publications

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“…The possible role of the Smurf1 protein in an anti-inflammation process is supported by a recent report about on Smurf1-mediated ubiquitination and degradation of TRAF family proteins 39 . Our findings add to the diverse roles of the Smurf proteins, which include their traditional role as antagonists of TGF-β/bone morphogenic protein signalling, and a more recently discovered role in planar cell polarity through the non-canonical Wnt signalling pathway 40 . Second, we provide further evidence for a distinct role of Smad6 from Smad7, although both are anti-inflammatory mediators.…”

Section: Discussionmentioning

confidence: 66%

Smad6-specific recruitment of Smurf E3 ligases mediates TGF-β1-induced degradation of MyD88 in TLR4 signalling

et al. 2011

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Transforming growth factor-β (TGF-β) is a potent anti-inflammatory cytokine that regulates interleukin-1 receptor and Toll-like receptor (TLR) signalling. Here we show a novel mechanism where TGF-β1-induced K48-linked polyubiquitination and degradation of the adaptor myD88 protein is dependent on the smad6 protein, but not smad7, and mediated by recruitment of the smad ubiquitin regulator factor proteins, smurf1 and smurf2, which have E3-ubiquitin ligase activity. smurf1 interaction with myD88 appears to be mediated by smad6, and smurf2 interaction by smurf1. Knockdown of endogenous smurf1 or smurf2 by RnA interference significantly suppresses the anti-inflammatory effects of TGF-β1 by preventing lipopolysaccharide-induced nF-κB nuclear translocation, resulting in de-suppression of proinflammatory gene expression. similar effects are observed on the lipoteichoic-acid-induced TLR2 pathway, which is also myD88-dependent, but not the myD88-independent TLR3 pathway. Thus, our results suggest that myD88 degradation driven by the smad6-smurf pathway is a novel mechanism for TGF-β1-mediated negative regulation of myD88-dependent pro-inflammatory signalling.

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Section: Discussionmentioning

confidence: 66%

Smad6-specific recruitment of Smurf E3 ligases mediates TGF-β1-induced degradation of MyD88 in TLR4 signalling

et al. 2011

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“…Other combined mutations have also shown a percentage of exencephaly, including Dvl3 6 ; Vangl2 Lpþ (5 cranio, 2 exen /22), whereas Dvl3 À/À ; Vangl2 Lp/þ showed only craniorachischisis (6/16) on a mixed genetic background with 129S6 (Etheridge et al, 2008). Smurf ubiquitin ligases1 and 2, involved in degradation of the PCP core protein Prickle1, show exencephaly and/or spina bifida as well as inner ear defects in 25% of embryos which lose three of four Smurf alleles (Narimatsu et al, 2009). The crooked tail allele of Lrp6 allele on a mixed DBA/2J x A/J genetic background shows $20-30% exencephalic embryos, and not craniorachischisis or spina bifida (Carter et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Role of chromatin remodeling gene Cecr2 in neurulation and inner ear development

Dawe

Kooistra

Fairbridge

et al. 2011

Developmental Dynamics

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The loss of Cecr2, which encodes a chromatin remodeling protein, has been associated with the neural tube defect (NTD) exencephaly and open eyelids in mice. Here, we show that two independent mutations of Cecr2 are also associated with specific inner ear defects. Homozygous mutant 18.5 days post coitus (dpc) fetuses exhibited smaller cochleae as well as rotational defects of sensory cells and extra cell rows in the inner ear reminiscent of planar cell polarity (PCP) mutants. Cecr2 was expressed in the neuroepithelium, head mesenchyme, and the cochlear floor. Although limited genetic interaction for NTDs was seen with Vangl2, a microarray analysis of PCP genes did not reveal a direct connection to this pathway. The mechanism of Cecr2 action in neurogenesis and inner ear development is likely complex.

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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.

125

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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Regulation of Planar Cell Polarity by Smurf Ubiquitin Ligases

Cited by 303 publications

References 46 publications

Smad6-specific recruitment of Smurf E3 ligases mediates TGF-β1-induced degradation of MyD88 in TLR4 signalling

Smad6-specific recruitment of Smurf E3 ligases mediates TGF-β1-induced degradation of MyD88 in TLR4 signalling

Role of chromatin remodeling gene Cecr2 in neurulation and inner ear development

Peptide and small molecule inhibitors of HECT-type ubiquitin ligases

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