title: HECT domain-containing E3 ubiquitin ligase NEDD4L negatively regulates Wnt signaling by targeting dishevelled for proteasomal degradation.
abstract: 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.
authors: The State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China.
authors: Yi
authors: Y
authors: Ding
authors: School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors: Yan
authors: Y
authors: Zhang
authors: The State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China.
authors: Chao
authors: C
authors: Xu
authors: School of Life Sciences, Tsinghua University, Beijing 100084, China. Electronic address: qhtaolab@tsinghua.edu.cn.
authors: Qing-Hua
authors: QH
authors: Tao
authors: The State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China. Electronic address: ygchen@tsinghua.edu.cn.
authors: Ye-Guang
authors: YG
authors: Chen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D020816:Amino Acid Motifs; D000818:Animals; D017124:Conserved Sequence; D000072261:Dishevelled Proteins; D056827:Endosomal Sorting Complexes Required for Transport / Q000502:physiology*; D025461:Feedback, Physiological; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D000075702:Nedd4 Ubiquitin Protein Ligases; D010750:Phosphoproteins / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*; D054875:Ubiquitination; D060449:Wnt Signaling Pathway; D029867:Xenopus Proteins; D014982:Xenopus laevis / Q000196:embryology; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C000606586:DVL1 protein, Xenopus; C000606581:DVL2 protein, human; D000072261:Dishevelled Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D010750:Phosphoproteins; C107953:RAC1 protein, human; D029867:Xenopus Proteins; C066737:RHOA protein, human; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618485:Nedd4L protein, human; C000618460:nedd4l protein, Xenopus; D044767:Ubiquitin-Protein Ligases; D048031:JNK Mitogen-Activated Protein Kinases; D046988:Proteasome Endopeptidase Complex; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein
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