PMID- 22575959
OWN - NLM
STAT- MEDLINE
DCOM- 20120625
LR  - 20230108
IS  - 1476-4687 (Electronic)
IS  - 0028-0836 (Linking)
VI  - 485
IP  - 7397
DP  - 2012 Apr 29
TI  - ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner.
PG  - 195-200
LID - 10.1038/nature11019 [doi]
AB  - R-spondin proteins strongly potentiate Wnt signalling and function as stem-cell 
      growth factors. Despite the biological and therapeutic significance, the 
      molecular mechanism of R-spondin action remains unclear. Here we show that the 
      cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and 
      its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt 
      signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt 
      signalling by promoting the turnover of frizzled and LRP6. Inhibition of ZNRF3 
      enhances Wnt/beta-catenin signalling and disrupts Wnt/planar cell polarity 
      signalling in vivo. Notably, R-spondin mimics ZNRF3 inhibition by increasing the 
      membrane level of Wnt receptors. Mechanistically, R-spondin interacts with the 
      extracellular domain of ZNRF3 and induces the association between ZNRF3 and LGR4, 
      which results in membrane clearance of ZNRF3. These data suggest that R-spondin 
      enhances Wnt signalling by inhibiting ZNRF3. Our study provides new mechanistic 
      insights into the regulation of Wnt receptor turnover, and reveals ZNRF3 as a 
      tractable target for therapeutic exploration.
FAU - Hao, Huai-Xiang
AU  - Hao HX
AD  - Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, 
      Massachusetts 02139, USA.
FAU - Xie, Yang
AU  - Xie Y
FAU - Zhang, Yue
AU  - Zhang Y
FAU - Charlat, Olga
AU  - Charlat O
FAU - Oster, Emma
AU  - Oster E
FAU - Avello, Monika
AU  - Avello M
FAU - Lei, Hong
AU  - Lei H
FAU - Mickanin, Craig
AU  - Mickanin C
FAU - Liu, Dong
AU  - Liu D
FAU - Ruffner, Heinz
AU  - Ruffner H
FAU - Mao, Xiaohong
AU  - Mao X
FAU - Ma, Qicheng
AU  - Ma Q
FAU - Zamponi, Raffaella
AU  - Zamponi R
FAU - Bouwmeester, Tewis
AU  - Bouwmeester T
FAU - Finan, Peter M
AU  - Finan PM
FAU - Kirschner, Marc W
AU  - Kirschner MW
FAU - Porter, Jeffery A
AU  - Porter JA
FAU - Serluca, Fabrizio C
AU  - Serluca FC
FAU - Cong, Feng
AU  - Cong F
LA  - eng
PT  - Journal Article
DEP - 20120429
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Frizzled Receptors)
RN  - 0 (LGR4 protein, human)
RN  - 0 (LRP6 protein, human)
RN  - 0 (Low Density Lipoprotein Receptor-Related Protein-6)
RN  - 0 (Oncogene Proteins)
RN  - 0 (RSPO1 protein, human)
RN  - 0 (Receptors, G-Protein-Coupled)
RN  - 0 (Receptors, Wnt)
RN  - 0 (Thrombospondins)
RN  - 0 (beta Catenin)
RN  - EC 2.3.2.27 (RNF43 protein, human)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
RN  - EC 2.3.2.27 (ZNRF3 protein, human)
RN  - EC 2.3.2.27 (Znrf3 protein, mouse)
SB  - IM
CIN - Nat Rev Mol Cell Biol. 2012 Jun;13(6):342. PMID: 22617469
CIN - Nat Biotechnol. 2012 Sep;30(9):835-6. PMID: 22965053
CIN - Curr Biol. 2012 Oct 9;22(19):R849-51. PMID: 23058807
MH  - Animals
MH  - Cell Polarity/physiology
MH  - Colorectal Neoplasms/genetics
MH  - DNA-Binding Proteins/deficiency/genetics/metabolism
MH  - Feedback, Physiological
MH  - Female
MH  - Frizzled Receptors/metabolism
MH  - HEK293 Cells
MH  - Humans
MH  - Low Density Lipoprotein Receptor-Related Protein-6/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Knockout
MH  - Oncogene Proteins/deficiency/genetics/metabolism
MH  - Protein Stability
MH  - Protein Structure, Tertiary
MH  - Receptors, G-Protein-Coupled/deficiency/genetics/metabolism
MH  - Receptors, Wnt/*metabolism
MH  - Thrombospondins/*metabolism
MH  - Ubiquitin-Protein Ligases/chemistry/*deficiency/genetics/*metabolism
MH  - Ubiquitination
MH  - Wnt Signaling Pathway
MH  - Xenopus
MH  - Zebrafish
MH  - beta Catenin/metabolism
EDAT- 2012/05/12 06:00
MHDA- 2012/06/26 06:00
CRDT- 2012/05/12 06:00
PHST- 2011/10/10 00:00 [received]
PHST- 2012/03/06 00:00 [accepted]
PHST- 2012/05/12 06:00 [entrez]
PHST- 2012/05/12 06:00 [pubmed]
PHST- 2012/06/26 06:00 [medline]
AID - nature11019 [pii]
AID - 10.1038/nature11019 [doi]
PST - epublish
SO  - Nature. 2012 Apr 29;485(7397):195-200. doi: 10.1038/nature11019.