HECT domain-containing E3 ubiquitin ligase NEDD4L negatively regulates Wnt signaling by targeting dishevelled for proteasomal degradation

Yi Ding; Yan Zhang; Chao Xu; Qing-Hua Tao; Ye-Guang Chen

doi:10.1074/jbc.M112.433185

HECT domain-containing E3 ubiquitin ligase NEDD4L negatively regulates Wnt signaling by targeting dishevelled for proteasomal degradation

J Biol Chem. 2013 Mar 22;288(12):8289-8298. doi: 10.1074/jbc.M112.433185. Epub 2013 Feb 9.

Authors

Yi Ding¹, Yan Zhang², Chao Xu¹, Qing-Hua Tao³, Ye-Guang Chen⁴

Affiliations

¹ The State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China.
² School of Life Sciences, Tsinghua University, Beijing 100084, China.
³ School of Life Sciences, Tsinghua University, Beijing 100084, China. Electronic address: [email protected].
⁴ The State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China. Electronic address: [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / metabolism*
Amino Acid Motifs
Animals
Conserved Sequence
Dishevelled Proteins
Endosomal Sorting Complexes Required for Transport / physiology*
Feedback, Physiological
HEK293 Cells
HeLa Cells
Humans
JNK Mitogen-Activated Protein Kinases / metabolism
Nedd4 Ubiquitin Protein Ligases
Phosphoproteins / metabolism*
Proteasome Endopeptidase Complex / metabolism*
Protein Binding
Protein Structure, Tertiary
Proteolysis
Ubiquitin-Protein Ligases / physiology*
Ubiquitination
Wnt Signaling Pathway*
Xenopus Proteins
Xenopus laevis / embryology
rac1 GTP-Binding Protein / metabolism
rhoA GTP-Binding Protein / metabolism

Substances

Adaptor Proteins, Signal Transducing
DVL1 protein, Xenopus
DVL2 protein, human
Dishevelled Proteins
Endosomal Sorting Complexes Required for Transport
Phosphoproteins
RAC1 protein, human
Xenopus Proteins
RHOA protein, human
Nedd4 Ubiquitin Protein Ligases
Nedd4L protein, human
nedd4l protein, Xenopus
Ubiquitin-Protein Ligases
JNK Mitogen-Activated Protein Kinases
Proteasome Endopeptidase Complex
rac1 GTP-Binding Protein
rhoA GTP-Binding Protein