Nucleoredoxin sustains Wnt/β-catenin signaling by retaining a pool of inactive dishevelled protein.
Overexpression of Dishevelled (Dvl), an essential component of the Wnt signaling pathway, is frequently associated with tumors, and thus the Dvl protein level must be tightly controlled to sustain Wnt signaling without causing tumors. Kelch-like 12 (KLHL12) targets Dvl for ubiquitination and degradation, suggesting its potential importance in avoiding aberrant Dvl overexpression. However, the regulatory mechanism of the KLHL12 activity remained elusive. We show here that nucleoredoxin (NRX) determines the Dvl protein level, which is revealed by analyses on NRX(-/-) mice showing skeletal and cardiovascular defects. Consistent with the previously reported Dvl-inhibiting function of NRX, Wnt/β-catenin signaling is hyperactivated in NRX(-/-) osteoblasts. However, the signal activity is suppressed in cardiac cells, where KLHL12 is highly expressed. Biochemical analyses reveal that Dvl is rapidly degraded by accelerated ubiquitination in NRX(-/-) mouse embryonic fibroblasts, and they fail to activate Wnt/β-catenin signaling in response to Wnt ligands. Moreover, experiments utilizing purified proteins show that NRX expels KLHL12 from Dvl and inhibits ubiquitination. These findings reveal an unexpected function of NRX, retaining a pool of inactive Dvl for robust activation of Wnt/β-catenin signaling upon Wnt stimulation.
Funato
Yosuke
Y
Laboratory of Intracellular Signaling, Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan.
Terabayashi
Takeshi
T
Sakamoto
Reiko
R
Okuzaki
Daisuke
D
Ichise
Hirotake
H
Nojima
Hiroshi
H
Yoshida
Nobuaki
N
Miki
Hiroaki
H
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D000072261:Dishevelled Proteins; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D010006:Osteoblasts / Q000378:metabolism; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010750:Phosphoproteins / Q000378:metabolism; D015398:Signal Transduction; D054875:Ubiquitination; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D000072261:Dishevelled Proteins; C529567:KLHL12 protein, mouse; D009687:Nuclear Proteins; D010750:Phosphoproteins; D051153:Wnt Proteins; D051176:beta Catenin; D010088:Oxidoreductases; C105231:nucleoredoxin