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Wnt signaling plays a pivotal role in embryogenesis and tissue homeostasis. Dishevelled (Dvl) is a central mediator for both Wnt/β-catenin and Wnt/planar cell polarity pathways. NEDD4L, an E3 ubiquitin ligase, has been shown to regulate ion channel activity, cell signaling, and cell polarity. Here, we report a novel role of NEDD4L in the regulation of Wnt signaling. NEDD4L induces Dvl2 polyubiquitination and targets Dvl2 for proteasomal degradation. Interestingly, the NEDD4L-mediated ubiquitination of Dvl2 is Lys-6, Lys-27, and Lys-29 linked but not typical Lys-48-linked ubiquitination. Consistent with the role of Dvl in both Wnt/β-catenin and Wnt/planar cell polarity signaling, NEDD4L regulates the cellular β-catenin level and Rac1, RhoA, and JNK activities. We have further identified a hierarchical regulation that Wnt5a induces JNK-mediated phosphorylation of NEDD4L, which in turn promotes its ability to degrade Dvl2. Finally, we show that NEDD4L inhibits Dvl2-induced axis duplication in Xenopus embryos. Our work thus demonstrates that NEDD4L is a negative feedback regulator of Wnt signaling.
Angers,
The KLHL12-Cullin-3 ubiquitin ligase negatively regulates the Wnt-beta-catenin pathway by targeting Dishevelled for degradation.
2006, Pubmed,
Xenbase
Angers,
The KLHL12-Cullin-3 ubiquitin ligase negatively regulates the Wnt-beta-catenin pathway by targeting Dishevelled for degradation.
2006,
Pubmed
,
Xenbase Bernassola,
The HECT family of E3 ubiquitin ligases: multiple players in cancer development.
2008,
Pubmed Boase,
Respiratory distress and perinatal lethality in Nedd4-2-deficient mice.
2011,
Pubmed Cao,
Nedd4 controls animal growth by regulating IGF-1 signaling.
2008,
Pubmed Clevers,
Wnt/β-catenin signaling and disease.
2012,
Pubmed Dibbens,
NEDD4-2 as a potential candidate susceptibility gene for epileptic photosensitivity.
2007,
Pubmed
,
Xenbase Dwyer,
Age-dependent alterations in spermatogenesis in itchy mice.
2012,
Pubmed Fotia,
The ubiquitin-protein ligases Nedd4 and Nedd4-2 show similar ubiquitin-conjugating enzyme specificities.
2006,
Pubmed Fouladkou,
The ubiquitin ligase Nedd4-1 is required for heart development and is a suppressor of thrombospondin-1.
2010,
Pubmed Ganner,
Regulation of ciliary polarity by the APC/C.
2009,
Pubmed
,
Xenbase Gao,
Ubiquitin ligase Nedd4L targets activated Smad2/3 to limit TGF-beta signaling.
2009,
Pubmed Gao,
Autophagy negatively regulates Wnt signalling by promoting Dishevelled degradation.
2010,
Pubmed Gao,
Dishevelled: The hub of Wnt signaling.
2010,
Pubmed Goodrich,
Principles of planar polarity in animal development.
2011,
Pubmed Gray,
Planar cell polarity: coordinating morphogenetic cell behaviors with embryonic polarity.
2011,
Pubmed Hallows,
Phosphopeptide screen uncovers novel phosphorylation sites of Nedd4-2 that potentiate its inhibition of the epithelial Na+ channel.
2010,
Pubmed
,
Xenbase He,
Down-regulation of Nedd4L is associated with the aggressive progression and worse prognosis of malignant glioma.
2012,
Pubmed Hu,
Nedd4L expression is downregulated in prostate cancer compared to benign prostatic hyperplasia.
2009,
Pubmed Jiang,
Genomic profiles in stage I primary non small cell lung cancer using comparative genomic hybridization analysis of cDNA microarrays.
2004,
Pubmed Kamnasaran,
Genetic analysis of psychiatric disorders associated with human chromosome 18.
2003,
Pubmed Kimura,
Deletion of the ubiquitin ligase Nedd4L in lung epithelia causes cystic fibrosis-like disease.
2011,
Pubmed Kravtsova-Ivantsiv,
Non-canonical ubiquitin-based signals for proteasomal degradation.
2012,
Pubmed Lei,
The Bax subfamily of Bcl2-related proteins is essential for apoptotic signal transduction by c-Jun NH(2)-terminal kinase.
2002,
Pubmed Liao,
Jun NH2-terminal kinase (JNK) prevents nuclear beta-catenin accumulation and regulates axis formation in Xenopus embryos.
2006,
Pubmed
,
Xenbase MacDonald,
Wnt/beta-catenin signaling: components, mechanisms, and diseases.
2009,
Pubmed
,
Xenbase Melino,
Itch: a HECT-type E3 ligase regulating immunity, skin and cancer.
2008,
Pubmed Metzger,
HECT and RING finger families of E3 ubiquitin ligases at a glance.
2012,
Pubmed Miyazaki,
NEDL1, a novel ubiquitin-protein isopeptide ligase for dishevelled-1, targets mutant superoxide dismutase-1.
2004,
Pubmed Mizutani,
Upregulation and overexpression of DVL1, the human counterpart of the Drosophila dishevelled gene, in prostate cancer.
2005,
Pubmed Nandadasa,
N- and E-cadherins in Xenopus are specifically required in the neural and non-neural ectoderm, respectively, for F-actin assembly and morphogenetic movements.
2009,
Pubmed
,
Xenbase Nethe,
Rac1 acts in conjunction with Nedd4 and dishevelled-1 to promote maturation of cell-cell contacts.
2012,
Pubmed Perry,
The itchy locus encodes a novel ubiquitin protein ligase that is disrupted in a18H mice.
1998,
Pubmed Pulvirenti,
Dishevelled 2 signaling promotes self-renewal and tumorigenicity in human gliomas.
2011,
Pubmed Rao,
Paternally derived translocation t(8;18)(q22.1;q22)pat associated in a patient with developmental delay: Case report and review.
2010,
Pubmed Rotin,
Physiological functions of the HECT family of ubiquitin ligases.
2009,
Pubmed Sharma,
Malin regulates Wnt signaling pathway through degradation of dishevelled2.
2012,
Pubmed Simons,
Planar cell polarity signaling: from fly development to human disease.
2008,
Pubmed Snyder,
Down-regulating destruction: phosphorylation regulates the E3 ubiquitin ligase Nedd4-2.
2009,
Pubmed Uematsu,
Activation of the Wnt pathway in non small cell lung cancer: evidence of dishevelled overexpression.
2003,
Pubmed Van Campenhout,
Dlg3 trafficking and apical tight junction formation is regulated by nedd4 and nedd4-2 e3 ubiquitin ligases.
2011,
Pubmed Wallingford,
The developmental biology of Dishevelled: an enigmatic protein governing cell fate and cell polarity.
2005,
Pubmed Wallingford,
Planar cell polarity and the developmental control of cell behavior in vertebrate embryos.
2012,
Pubmed Wang,
The Nedd4-like ubiquitin E3 ligases target angiomotin/p130 to ubiquitin-dependent degradation.
2012,
Pubmed Wei,
The E3 ubiquitin ligase ITCH negatively regulates canonical Wnt signaling by targeting dishevelled protein.
2012,
Pubmed Wen,
Loss of Dact1 disrupts planar cell polarity signaling by altering dishevelled activity and leads to posterior malformation in mice.
2010,
Pubmed Yang,
Nedd4 and Nedd4-2: closely related ubiquitin-protein ligases with distinct physiological functions.
2010,
Pubmed Zhang,
Muscle atrophy and motor neuron degeneration in human NEDL1 transgenic mice.
2011,
Pubmed
