The KLHL12-Cullin-3 ubiquitin ligase negatively regulates the Wnt-beta-catenin pathway by targeting Dishevelled for degradation.
Dishevelled is a conserved protein that interprets signals received by Frizzled receptors. Using a tandem-affinity purification strategy and mass spectrometry we have identified proteins associated with Dishevelled, including a Cullin-3 ubiquitin ligase complex containing the Broad Complex, Tramtrack and Bric à Brac (BTB) protein Kelch-like 12 (KLHL12). This E3 ubiquitin ligase complex is recruited to Dishevelled in a Wnt-dependent manner that promotes its poly-ubiquitination and degradation. Functional analyses demonstrate that regulation of Dishevelled by this ubiquitin ligase antagonizes the Wnt-beta-catenin pathway in cultured cells, as well as in Xenopus and zebrafish embryos. Considered with evidence that the distinct Cullin-1 based SCF(beta-TrCP)complex regulates beta-catenin stability, our data on the stability of Dishevelled demonstrates that two distinct ubiquitin ligase complexes regulate the Wnt-beta-catenin pathway.
Howard Hughes Medical Institute, University of Washington School of Medicine, Box 357370, Seattle, WA 98195, USA.
Stephane
S
Angers
Chris J
CJ
Thorpe
Travis L
TL
Biechele
Seth J
SJ
Goldenberg
Ning
N
Zheng
Michael J
MJ
MacCoss
Randall T
RT
Moon
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000502:physiology*; D002460:Cell Line; D002846:Chromatography, Affinity; D044842:Cullin Proteins / Q000502:physiology*; D000072261:Dishevelled Proteins; D004625:Embryo, Nonmammalian / Q000378:metabolism; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007668:Kidney / Q000166:cytology; D008856:Microscopy, Fluorescence; D010750:Phosphoproteins / Q000378:metabolism*; D015398:Signal Transduction; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*; D051153:Wnt Proteins / Q000378:metabolism*; D029867:Xenopus Proteins / Q000502:physiology*; D014982:Xenopus laevis / Q000196:embryology; D015027:Zebrafish / Q000196:embryology; D029961:Zebrafish Proteins / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C503645:CUL3 protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D044842:Cullin Proteins; D000072261:Dishevelled Proteins; D047908:Intracellular Signaling Peptides and Proteins; C510247:KLHL12 protein, Xenopus; C510248:KLHL12 protein, zebrafish; D010750:Phosphoproteins; D025801:Ubiquitin; D051153:Wnt Proteins; D029867:Xenopus Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; D044767:Ubiquitin-Protein Ligases