ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner
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...
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| Veröffentlicht in: | Nature (London) 2012-05, Vol.485 (7397), p.195-200 |
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| creator | Hao, Huai-Xiang Xie, Yang Zhang, Yue Charlat, Olga Oster, Emma Avello, Monika Lei, Hong Mickanin, Craig Liu, Dong Ruffner, Heinz Mao, Xiaohong Ma, Qicheng Zamponi, Raffaella Bouwmeester, Tewis Finan, Peter M. Kirschner, Marc W. Porter, Jeffery A. Serluca, Fabrizio C. Cong, Feng |
| description | 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/β-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.
ZNRF3 and RNF43 are identified as negative feedback regulators of Wnt signalling; the stem-cell growth factor R-spondin is shown to potentiate Wnt signalling by inhibiting ZNRF3.
ZNRF3 protein inhibits Wnt signalling
The R-spondin proteins are secreted molecules that function as stem-cell growth factors and potentiate Wnt signalling by binding LGR4 family receptors, but their precise mechanism of action remains unclear. Here, the transmembrane E3 ubiquitin ligase ZNRF3 is identified as an inhibitor of Wnt signalling that acts by promoting the turnover of Wnt receptors. R-spondin potentiates Wnt signalling by inhibiting ZNRF3 in a mechanism dependent on LGR4, resulting in the accumulation of Wnt receptors. Given the importance of Wnt signalling in cancer, ZNRF3 may be a target for therapeutic intervention. |
| doi_str_mv | 10.1038/nature11019 |
| format | Article |
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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.
ZNRF3 and RNF43 are identified as negative feedback regulators of Wnt signalling; the stem-cell growth factor R-spondin is shown to potentiate Wnt signalling by inhibiting ZNRF3.
ZNRF3 protein inhibits Wnt signalling
The R-spondin proteins are secreted molecules that function as stem-cell growth factors and potentiate Wnt signalling by binding LGR4 family receptors, but their precise mechanism of action remains unclear. Here, the transmembrane E3 ubiquitin ligase ZNRF3 is identified as an inhibitor of Wnt signalling that acts by promoting the turnover of Wnt receptors. R-spondin potentiates Wnt signalling by inhibiting ZNRF3 in a mechanism dependent on LGR4, resulting in the accumulation of Wnt receptors. Given the importance of Wnt signalling in cancer, ZNRF3 may be a target for therapeutic intervention.</description><identifier>ISSN: 0028-0836</identifier><identifier>EISSN: 1476-4687</identifier><identifier>DOI: 10.1038/nature11019</identifier><identifier>PMID: 22575959</identifier><identifier>CODEN: NATUAS</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/136/532 ; 631/80/85 ; 631/80/86 ; 692/700/565/1436 ; Animals ; beta Catenin - metabolism ; Biological and medical sciences ; Cancer ; Cell physiology ; Cell Polarity - physiology ; Cell receptors ; Cell structures and functions ; Cellular signal transduction ; Colorectal Neoplasms - genetics ; DNA-Binding Proteins - deficiency ; DNA-Binding Proteins - genetics ; DNA-Binding Proteins - metabolism ; Feedback, Physiological ; Female ; Frizzled Receptors - metabolism ; Fundamental and applied biological sciences. Psychology ; Gene expression ; Genetic aspects ; Growth factors ; Health aspects ; HEK293 Cells ; Humanities and Social Sciences ; Humans ; Kinases ; Low Density Lipoprotein Receptor-Related Protein-6 - metabolism ; Male ; Membrane proteins ; Mice ; Mice, Knockout ; Miscellaneous ; Molecular and cellular biology ; multidisciplinary ; Oncogene Proteins - deficiency ; Oncogene Proteins - genetics ; Oncogene Proteins - metabolism ; Physiological aspects ; Protein Stability ; Protein Structure, Tertiary ; Proteins ; Receptors, G-Protein-Coupled - deficiency ; Receptors, G-Protein-Coupled - genetics ; Receptors, G-Protein-Coupled - metabolism ; Receptors, Wnt - metabolism ; Rodents ; Science ; Science (multidisciplinary) ; Signal transduction ; Thrombospondins - metabolism ; Ubiquitin ; Ubiquitin-Protein Ligases - chemistry ; Ubiquitin-Protein Ligases - deficiency ; Ubiquitin-Protein Ligases - genetics ; Ubiquitin-Protein Ligases - metabolism ; Ubiquitination ; Wnt Signaling Pathway ; Xenopus ; Zebrafish</subject><ispartof>Nature (London), 2012-05, Vol.485 (7397), p.195-200</ispartof><rights>Springer Nature Limited 2012</rights><rights>2015 INIST-CNRS</rights><rights>COPYRIGHT 2012 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group May 10, 2012</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c550t-d938626502e051fe2bf3d81725163c4329cb53cf454a983d07df5d24f82e268e3</citedby><cites>FETCH-LOGICAL-c550t-d938626502e051fe2bf3d81725163c4329cb53cf454a983d07df5d24f82e268e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/nature11019$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/nature11019$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=25857050$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22575959$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hao, Huai-Xiang</creatorcontrib><creatorcontrib>Xie, Yang</creatorcontrib><creatorcontrib>Zhang, Yue</creatorcontrib><creatorcontrib>Charlat, Olga</creatorcontrib><creatorcontrib>Oster, Emma</creatorcontrib><creatorcontrib>Avello, Monika</creatorcontrib><creatorcontrib>Lei, Hong</creatorcontrib><creatorcontrib>Mickanin, Craig</creatorcontrib><creatorcontrib>Liu, Dong</creatorcontrib><creatorcontrib>Ruffner, Heinz</creatorcontrib><creatorcontrib>Mao, Xiaohong</creatorcontrib><creatorcontrib>Ma, Qicheng</creatorcontrib><creatorcontrib>Zamponi, Raffaella</creatorcontrib><creatorcontrib>Bouwmeester, Tewis</creatorcontrib><creatorcontrib>Finan, Peter M.</creatorcontrib><creatorcontrib>Kirschner, Marc W.</creatorcontrib><creatorcontrib>Porter, Jeffery A.</creatorcontrib><creatorcontrib>Serluca, Fabrizio C.</creatorcontrib><creatorcontrib>Cong, Feng</creatorcontrib><title>ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner</title><title>Nature (London)</title><addtitle>Nature</addtitle><addtitle>Nature</addtitle><description>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/β-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.
ZNRF3 and RNF43 are identified as negative feedback regulators of Wnt signalling; the stem-cell growth factor R-spondin is shown to potentiate Wnt signalling by inhibiting ZNRF3.
ZNRF3 protein inhibits Wnt signalling
The R-spondin proteins are secreted molecules that function as stem-cell growth factors and potentiate Wnt signalling by binding LGR4 family receptors, but their precise mechanism of action remains unclear. Here, the transmembrane E3 ubiquitin ligase ZNRF3 is identified as an inhibitor of Wnt signalling that acts by promoting the turnover of Wnt receptors. R-spondin potentiates Wnt signalling by inhibiting ZNRF3 in a mechanism dependent on LGR4, resulting in the accumulation of Wnt receptors. Given the importance of Wnt signalling in cancer, ZNRF3 may be a target for therapeutic intervention.</description><subject>631/136/532</subject><subject>631/80/85</subject><subject>631/80/86</subject><subject>692/700/565/1436</subject><subject>Animals</subject><subject>beta Catenin - metabolism</subject><subject>Biological and medical sciences</subject><subject>Cancer</subject><subject>Cell physiology</subject><subject>Cell Polarity - physiology</subject><subject>Cell receptors</subject><subject>Cell structures and functions</subject><subject>Cellular signal transduction</subject><subject>Colorectal Neoplasms - genetics</subject><subject>DNA-Binding Proteins - deficiency</subject><subject>DNA-Binding Proteins - genetics</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Feedback, Physiological</subject><subject>Female</subject><subject>Frizzled Receptors - metabolism</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Gene expression</subject><subject>Genetic aspects</subject><subject>Growth factors</subject><subject>Health aspects</subject><subject>HEK293 Cells</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Kinases</subject><subject>Low Density Lipoprotein Receptor-Related Protein-6 - metabolism</subject><subject>Male</subject><subject>Membrane proteins</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Miscellaneous</subject><subject>Molecular and cellular biology</subject><subject>multidisciplinary</subject><subject>Oncogene Proteins - deficiency</subject><subject>Oncogene Proteins - genetics</subject><subject>Oncogene Proteins - metabolism</subject><subject>Physiological aspects</subject><subject>Protein Stability</subject><subject>Protein Structure, Tertiary</subject><subject>Proteins</subject><subject>Receptors, G-Protein-Coupled - deficiency</subject><subject>Receptors, G-Protein-Coupled - genetics</subject><subject>Receptors, G-Protein-Coupled - metabolism</subject><subject>Receptors, Wnt - metabolism</subject><subject>Rodents</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Signal transduction</subject><subject>Thrombospondins - metabolism</subject><subject>Ubiquitin</subject><subject>Ubiquitin-Protein Ligases - chemistry</subject><subject>Ubiquitin-Protein Ligases - deficiency</subject><subject>Ubiquitin-Protein Ligases - genetics</subject><subject>Ubiquitin-Protein Ligases - metabolism</subject><subject>Ubiquitination</subject><subject>Wnt Signaling 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Academic</collection><jtitle>Nature (London)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hao, Huai-Xiang</au><au>Xie, Yang</au><au>Zhang, Yue</au><au>Charlat, Olga</au><au>Oster, Emma</au><au>Avello, Monika</au><au>Lei, Hong</au><au>Mickanin, Craig</au><au>Liu, Dong</au><au>Ruffner, Heinz</au><au>Mao, Xiaohong</au><au>Ma, Qicheng</au><au>Zamponi, Raffaella</au><au>Bouwmeester, Tewis</au><au>Finan, Peter M.</au><au>Kirschner, Marc W.</au><au>Porter, Jeffery A.</au><au>Serluca, Fabrizio C.</au><au>Cong, Feng</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner</atitle><jtitle>Nature (London)</jtitle><stitle>Nature</stitle><addtitle>Nature</addtitle><date>2012-05-10</date><risdate>2012</risdate><volume>485</volume><issue>7397</issue><spage>195</spage><epage>200</epage><pages>195-200</pages><issn>0028-0836</issn><eissn>1476-4687</eissn><coden>NATUAS</coden><abstract>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/β-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.
ZNRF3 and RNF43 are identified as negative feedback regulators of Wnt signalling; the stem-cell growth factor R-spondin is shown to potentiate Wnt signalling by inhibiting ZNRF3.
ZNRF3 protein inhibits Wnt signalling
The R-spondin proteins are secreted molecules that function as stem-cell growth factors and potentiate Wnt signalling by binding LGR4 family receptors, but their precise mechanism of action remains unclear. Here, the transmembrane E3 ubiquitin ligase ZNRF3 is identified as an inhibitor of Wnt signalling that acts by promoting the turnover of Wnt receptors. R-spondin potentiates Wnt signalling by inhibiting ZNRF3 in a mechanism dependent on LGR4, resulting in the accumulation of Wnt receptors. Given the importance of Wnt signalling in cancer, ZNRF3 may be a target for therapeutic intervention.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>22575959</pmid><doi>10.1038/nature11019</doi><tpages>6</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0028-0836 |
| ispartof | Nature (London), 2012-05, Vol.485 (7397), p.195-200 |
| issn | 0028-0836 1476-4687 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1012748115 |
| source | MEDLINE; Nature Journals Online; SpringerLink Journals - AutoHoldings |
| subjects | 631/136/532 631/80/85 631/80/86 692/700/565/1436 Animals beta Catenin - metabolism Biological and medical sciences Cancer Cell physiology Cell Polarity - physiology Cell receptors Cell structures and functions Cellular signal transduction Colorectal Neoplasms - genetics DNA-Binding Proteins - deficiency DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Feedback, Physiological Female Frizzled Receptors - metabolism Fundamental and applied biological sciences. Psychology Gene expression Genetic aspects Growth factors Health aspects HEK293 Cells Humanities and Social Sciences Humans Kinases Low Density Lipoprotein Receptor-Related Protein-6 - metabolism Male Membrane proteins Mice Mice, Knockout Miscellaneous Molecular and cellular biology multidisciplinary Oncogene Proteins - deficiency Oncogene Proteins - genetics Oncogene Proteins - metabolism Physiological aspects Protein Stability Protein Structure, Tertiary Proteins Receptors, G-Protein-Coupled - deficiency Receptors, G-Protein-Coupled - genetics Receptors, G-Protein-Coupled - metabolism Receptors, Wnt - metabolism Rodents Science Science (multidisciplinary) Signal transduction Thrombospondins - metabolism Ubiquitin Ubiquitin-Protein Ligases - chemistry Ubiquitin-Protein Ligases - deficiency Ubiquitin-Protein Ligases - genetics Ubiquitin-Protein Ligases - metabolism Ubiquitination Wnt Signaling Pathway Xenopus Zebrafish |
| title | ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-07T19%3A16%3A08IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=ZNRF3%20promotes%20Wnt%20receptor%20turnover%20in%20an%20R-spondin-sensitive%20manner&rft.jtitle=Nature%20(London)&rft.au=Hao,%20Huai-Xiang&rft.date=2012-05-10&rft.volume=485&rft.issue=7397&rft.spage=195&rft.epage=200&rft.pages=195-200&rft.issn=0028-0836&rft.eissn=1476-4687&rft.coden=NATUAS&rft_id=info:doi/10.1038/nature11019&rft_dat=%3Cgale_proqu%3EA290293654%3C/gale_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1015338849&rft_id=info:pmid/22575959&rft_galeid=A290293654&rfr_iscdi=true |