Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors
In vivo and in vitro studies show that the stem-cell E3 ubiquitin ligases RNF43 and ZNRF3 act as tumour suppressors in colorectal cancer models, and are involved in the negative regulation of the cancer-associated Wnt signalling pathway through limiting the cell-surface expression of Wnt receptors....
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| Veröffentlicht in: | Nature (London) 2012-08, Vol.488 (7413), p.665-669 |
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| creator | Koo, Bon-Kyoung Spit, Maureen Jordens, Ingrid Low, Teck Y. Stange, Daniel E. van de Wetering, Marc van Es, Johan H. Mohammed, Shabaz Heck, Albert J. R. Maurice, Madelon M. Clevers, Hans |
| description | In vivo
and
in vitro
studies show that the stem-cell E3 ubiquitin ligases RNF43 and ZNRF3 act as tumour suppressors in colorectal cancer models, and are involved in the negative regulation of the cancer-associated Wnt signalling pathway through limiting the cell-surface expression of Wnt receptors.
RNF43 protein in Wnt-linked colon cancer
Wnt signalling is critical for the function of intestinal stem cells; it also drives colorectal tumorigenesis. Bon-Kyoung Koo
et al
. find that two targets of Wnt signalling, the E3 ligases RNF43 and ZNFR3, are also important negative-feedback regulators of Wnt signalling. They act by limiting the cell-surface expression of Wnt receptors. Deletion of both genes in the mouse intestine leads to expansion of LGR5
+
intestinal stem cells and the development of adenomas. Furthermore, in human colon cancer cells, the expression of RNF43 reduces Wnt signalling. Mutated RNF43 has been found in human colorectal cancers, indicating that Wnt-pathway inhibitors that act at the level of Wnt secretion or Wnt-receptor activation may have therapeutic potential.
LGR5
+
stem cells reside at crypt bottoms, intermingled with Paneth cells that provide Wnt, Notch and epidermal growth factor signals
1
. Here we find that the related RNF43 and ZNRF3 transmembrane E3 ubiquitin ligases are uniquely expressed in LGR5
+
stem cells. Simultaneous deletion of the two genes encoding these proteins in the intestinal epithelium of mice induces rapidly growing adenomas containing high numbers of Paneth and LGR5
+
stem cells.
In vitro
, growth of organoids derived from these adenomas is arrested when Wnt secretion is inhibited, indicating a dependence of the adenoma stem cells on Wnt produced by adenoma Paneth cells. In the HEK293T human cancer cell line, expression of RNF43 blocks Wnt responses and targets surface-expressed frizzled receptors to lysosomes. In the
RNF43
-mutant colorectal cancer cell line HCT116, reconstitution of RNF43 expression removes its response to exogenous Wnt. We conclude that RNF43 and ZNRF3 reduce Wnt signals by selectively ubiquitinating frizzled receptors, thereby targeting these Wnt receptors for degradation. |
| doi_str_mv | 10.1038/nature11308 |
| format | Article |
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and
in vitro
studies show that the stem-cell E3 ubiquitin ligases RNF43 and ZNRF3 act as tumour suppressors in colorectal cancer models, and are involved in the negative regulation of the cancer-associated Wnt signalling pathway through limiting the cell-surface expression of Wnt receptors.
RNF43 protein in Wnt-linked colon cancer
Wnt signalling is critical for the function of intestinal stem cells; it also drives colorectal tumorigenesis. Bon-Kyoung Koo
et al
. find that two targets of Wnt signalling, the E3 ligases RNF43 and ZNFR3, are also important negative-feedback regulators of Wnt signalling. They act by limiting the cell-surface expression of Wnt receptors. Deletion of both genes in the mouse intestine leads to expansion of LGR5
+
intestinal stem cells and the development of adenomas. Furthermore, in human colon cancer cells, the expression of RNF43 reduces Wnt signalling. Mutated RNF43 has been found in human colorectal cancers, indicating that Wnt-pathway inhibitors that act at the level of Wnt secretion or Wnt-receptor activation may have therapeutic potential.
LGR5
+
stem cells reside at crypt bottoms, intermingled with Paneth cells that provide Wnt, Notch and epidermal growth factor signals
1
. Here we find that the related RNF43 and ZNRF3 transmembrane E3 ubiquitin ligases are uniquely expressed in LGR5
+
stem cells. Simultaneous deletion of the two genes encoding these proteins in the intestinal epithelium of mice induces rapidly growing adenomas containing high numbers of Paneth and LGR5
+
stem cells.
In vitro
, growth of organoids derived from these adenomas is arrested when Wnt secretion is inhibited, indicating a dependence of the adenoma stem cells on Wnt produced by adenoma Paneth cells. In the HEK293T human cancer cell line, expression of RNF43 blocks Wnt responses and targets surface-expressed frizzled receptors to lysosomes. In the
RNF43
-mutant colorectal cancer cell line HCT116, reconstitution of RNF43 expression removes its response to exogenous Wnt. We conclude that RNF43 and ZNRF3 reduce Wnt signals by selectively ubiquitinating frizzled receptors, thereby targeting these Wnt receptors for degradation.</description><identifier>ISSN: 0028-0836</identifier><identifier>EISSN: 1476-4687</identifier><identifier>DOI: 10.1038/nature11308</identifier><identifier>PMID: 22895187</identifier><identifier>CODEN: NATUAS</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/67/581 ; 631/80/313/1461 ; 631/80/86 ; Adenoma - metabolism ; Adenoma - pathology ; Animals ; beta Catenin - metabolism ; Biological and medical sciences ; Cell Proliferation ; Colorectal cancer ; Colorectal carcinoma ; Colorectal Neoplasms - metabolism ; Colorectal Neoplasms - pathology ; Development and progression ; DNA-Binding Proteins - deficiency ; DNA-Binding Proteins - genetics ; DNA-Binding Proteins - metabolism ; Endocytosis ; Epidermal growth factor ; Frizzled Receptors - metabolism ; Gene expression ; HEK293 Cells ; Humanities and Social Sciences ; Humans ; Kinases ; letter ; Lysosomes - metabolism ; Medical sciences ; Mice ; multidisciplinary ; Multiple tumors. Solid tumors. Tumors in childhood (general aspects) ; Mutation ; Oncogene Proteins - deficiency ; Oncogene Proteins - genetics ; Oncogene Proteins - metabolism ; Organoids - cytology ; Organoids - metabolism ; Organoids - pathology ; Paneth Cells - metabolism ; Paneth Cells - pathology ; Physiological aspects ; Proteins ; Receptors, G-Protein-Coupled - genetics ; Receptors, G-Protein-Coupled - metabolism ; Receptors, Wnt - antagonists & inhibitors ; Receptors, Wnt - metabolism ; Risk factors ; Rodents ; Science ; Science (multidisciplinary) ; Stem cells ; Stem Cells - cytology ; Stem Cells - enzymology ; Stem Cells - metabolism ; Tumor Suppressor Proteins - deficiency ; Tumor Suppressor Proteins - genetics ; Tumor Suppressor Proteins - metabolism ; Tumors ; Ubiquitin ; Ubiquitin - metabolism ; Ubiquitin-Protein Ligases - deficiency ; Ubiquitin-Protein Ligases - genetics ; Ubiquitin-Protein Ligases - metabolism ; Ubiquitination ; Wnt Signaling Pathway - drug effects</subject><ispartof>Nature (London), 2012-08, Vol.488 (7413), p.665-669</ispartof><rights>Springer Nature Limited 2012</rights><rights>2015 INIST-CNRS</rights><rights>COPYRIGHT 2012 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Aug 30, 2012</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c586t-1084c9a0383a56739c93ec2e5c986d0c198ccecaf4ec66be435a1e0573b374303</citedby><cites>FETCH-LOGICAL-c586t-1084c9a0383a56739c93ec2e5c986d0c198ccecaf4ec66be435a1e0573b374303</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/nature11308$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/nature11308$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27903,27904,41467,42536,51298</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=26291253$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22895187$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Koo, Bon-Kyoung</creatorcontrib><creatorcontrib>Spit, Maureen</creatorcontrib><creatorcontrib>Jordens, Ingrid</creatorcontrib><creatorcontrib>Low, Teck Y.</creatorcontrib><creatorcontrib>Stange, Daniel E.</creatorcontrib><creatorcontrib>van de Wetering, Marc</creatorcontrib><creatorcontrib>van Es, Johan H.</creatorcontrib><creatorcontrib>Mohammed, Shabaz</creatorcontrib><creatorcontrib>Heck, Albert J. R.</creatorcontrib><creatorcontrib>Maurice, Madelon M.</creatorcontrib><creatorcontrib>Clevers, Hans</creatorcontrib><title>Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors</title><title>Nature (London)</title><addtitle>Nature</addtitle><addtitle>Nature</addtitle><description>In vivo
and
in vitro
studies show that the stem-cell E3 ubiquitin ligases RNF43 and ZNRF3 act as tumour suppressors in colorectal cancer models, and are involved in the negative regulation of the cancer-associated Wnt signalling pathway through limiting the cell-surface expression of Wnt receptors.
RNF43 protein in Wnt-linked colon cancer
Wnt signalling is critical for the function of intestinal stem cells; it also drives colorectal tumorigenesis. Bon-Kyoung Koo
et al
. find that two targets of Wnt signalling, the E3 ligases RNF43 and ZNFR3, are also important negative-feedback regulators of Wnt signalling. They act by limiting the cell-surface expression of Wnt receptors. Deletion of both genes in the mouse intestine leads to expansion of LGR5
+
intestinal stem cells and the development of adenomas. Furthermore, in human colon cancer cells, the expression of RNF43 reduces Wnt signalling. Mutated RNF43 has been found in human colorectal cancers, indicating that Wnt-pathway inhibitors that act at the level of Wnt secretion or Wnt-receptor activation may have therapeutic potential.
LGR5
+
stem cells reside at crypt bottoms, intermingled with Paneth cells that provide Wnt, Notch and epidermal growth factor signals
1
. Here we find that the related RNF43 and ZNRF3 transmembrane E3 ubiquitin ligases are uniquely expressed in LGR5
+
stem cells. Simultaneous deletion of the two genes encoding these proteins in the intestinal epithelium of mice induces rapidly growing adenomas containing high numbers of Paneth and LGR5
+
stem cells.
In vitro
, growth of organoids derived from these adenomas is arrested when Wnt secretion is inhibited, indicating a dependence of the adenoma stem cells on Wnt produced by adenoma Paneth cells. In the HEK293T human cancer cell line, expression of RNF43 blocks Wnt responses and targets surface-expressed frizzled receptors to lysosomes. In the
RNF43
-mutant colorectal cancer cell line HCT116, reconstitution of RNF43 expression removes its response to exogenous Wnt. We conclude that RNF43 and ZNRF3 reduce Wnt signals by selectively ubiquitinating frizzled receptors, thereby targeting these Wnt receptors for degradation.</description><subject>631/67/581</subject><subject>631/80/313/1461</subject><subject>631/80/86</subject><subject>Adenoma - metabolism</subject><subject>Adenoma - pathology</subject><subject>Animals</subject><subject>beta Catenin - metabolism</subject><subject>Biological and medical sciences</subject><subject>Cell Proliferation</subject><subject>Colorectal cancer</subject><subject>Colorectal carcinoma</subject><subject>Colorectal Neoplasms - metabolism</subject><subject>Colorectal Neoplasms - pathology</subject><subject>Development and progression</subject><subject>DNA-Binding Proteins - deficiency</subject><subject>DNA-Binding Proteins - genetics</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Endocytosis</subject><subject>Epidermal growth factor</subject><subject>Frizzled Receptors - metabolism</subject><subject>Gene expression</subject><subject>HEK293 Cells</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Kinases</subject><subject>letter</subject><subject>Lysosomes - metabolism</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>multidisciplinary</subject><subject>Multiple tumors. Solid tumors. Tumors in childhood (general aspects)</subject><subject>Mutation</subject><subject>Oncogene Proteins - deficiency</subject><subject>Oncogene Proteins - genetics</subject><subject>Oncogene Proteins - metabolism</subject><subject>Organoids - cytology</subject><subject>Organoids - metabolism</subject><subject>Organoids - pathology</subject><subject>Paneth Cells - metabolism</subject><subject>Paneth Cells - pathology</subject><subject>Physiological aspects</subject><subject>Proteins</subject><subject>Receptors, G-Protein-Coupled - genetics</subject><subject>Receptors, G-Protein-Coupled - metabolism</subject><subject>Receptors, Wnt - antagonists & inhibitors</subject><subject>Receptors, Wnt - metabolism</subject><subject>Risk factors</subject><subject>Rodents</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Stem cells</subject><subject>Stem Cells - cytology</subject><subject>Stem Cells - enzymology</subject><subject>Stem Cells - metabolism</subject><subject>Tumor Suppressor Proteins - deficiency</subject><subject>Tumor Suppressor Proteins - genetics</subject><subject>Tumor Suppressor Proteins - metabolism</subject><subject>Tumors</subject><subject>Ubiquitin</subject><subject>Ubiquitin - metabolism</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 Pathway - drug effects</subject><issn>0028-0836</issn><issn>1476-4687</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp10tFr1DAcB_AiDndOn3yX4BAU7UyaJk0fj2NzgzFhngx8Kbn017OjTbr8UnD_vTl2ujut5CGQfPJL8k2S5BWjJ4xy9cnqMHpgjFP1JJmxvJBpLlXxNJlRmqmUKi4Pk-eIt5RSwYr8WXKYZaoUTBWz5Pty7N3oCY7D4AHReXJ9dZZz0iLRBAP0qYGuI6ecdO1aI5DwQwfS2no0gARs7cx9cBi5a8iNDcSDgSE4jy-Sg0Z3CC-3_VHy7ex0uThPL798vljML1MjlAwpoyo3pY434VrIgpem5GAyEKZUsqaGlcoYMLrJwUi5gpwLzYCKgq94kXPKj5J3D3UH7-5GwFD1LW4OrS24EasYUiFlzEVEevwXvY2Xt_F0G1VKkWdcPqq17qBqbeOC12ZTtJpzUSrBRZFFlU6oNVjwunMWmjYO7_k3E94M7V21i04mUGw19K2ZrPp-b0E0AX6GtR4Rq4uv1_v2w__tfHmzuJrUxjtED001-LbX_j5GtUlLVTsfL-rX22THVQ_1H_v7p0Xwdgs0Gt01XlvT4qOTWckywaP7-OAwTtk1-N0n-nffX0wL6c8</recordid><startdate>20120830</startdate><enddate>20120830</enddate><creator>Koo, Bon-Kyoung</creator><creator>Spit, Maureen</creator><creator>Jordens, Ingrid</creator><creator>Low, Teck Y.</creator><creator>Stange, Daniel E.</creator><creator>van de Wetering, Marc</creator><creator>van Es, Johan H.</creator><creator>Mohammed, Shabaz</creator><creator>Heck, Albert J. 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Solid tumors. Tumors in childhood (general aspects)</topic><topic>Mutation</topic><topic>Oncogene Proteins - deficiency</topic><topic>Oncogene Proteins - genetics</topic><topic>Oncogene Proteins - metabolism</topic><topic>Organoids - cytology</topic><topic>Organoids - metabolism</topic><topic>Organoids - pathology</topic><topic>Paneth Cells - metabolism</topic><topic>Paneth Cells - pathology</topic><topic>Physiological aspects</topic><topic>Proteins</topic><topic>Receptors, G-Protein-Coupled - genetics</topic><topic>Receptors, G-Protein-Coupled - metabolism</topic><topic>Receptors, Wnt - antagonists & inhibitors</topic><topic>Receptors, Wnt - metabolism</topic><topic>Risk factors</topic><topic>Rodents</topic><topic>Science</topic><topic>Science (multidisciplinary)</topic><topic>Stem cells</topic><topic>Stem Cells - cytology</topic><topic>Stem Cells - enzymology</topic><topic>Stem Cells - metabolism</topic><topic>Tumor Suppressor Proteins - deficiency</topic><topic>Tumor Suppressor Proteins - genetics</topic><topic>Tumor Suppressor Proteins - metabolism</topic><topic>Tumors</topic><topic>Ubiquitin</topic><topic>Ubiquitin - metabolism</topic><topic>Ubiquitin-Protein Ligases - deficiency</topic><topic>Ubiquitin-Protein Ligases - genetics</topic><topic>Ubiquitin-Protein Ligases - metabolism</topic><topic>Ubiquitination</topic><topic>Wnt Signaling Pathway - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Koo, Bon-Kyoung</creatorcontrib><creatorcontrib>Spit, Maureen</creatorcontrib><creatorcontrib>Jordens, Ingrid</creatorcontrib><creatorcontrib>Low, Teck Y.</creatorcontrib><creatorcontrib>Stange, Daniel E.</creatorcontrib><creatorcontrib>van de Wetering, Marc</creatorcontrib><creatorcontrib>van Es, Johan H.</creatorcontrib><creatorcontrib>Mohammed, Shabaz</creatorcontrib><creatorcontrib>Heck, Albert J. 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Academic</collection><jtitle>Nature (London)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Koo, Bon-Kyoung</au><au>Spit, Maureen</au><au>Jordens, Ingrid</au><au>Low, Teck Y.</au><au>Stange, Daniel E.</au><au>van de Wetering, Marc</au><au>van Es, Johan H.</au><au>Mohammed, Shabaz</au><au>Heck, Albert J. R.</au><au>Maurice, Madelon M.</au><au>Clevers, Hans</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors</atitle><jtitle>Nature (London)</jtitle><stitle>Nature</stitle><addtitle>Nature</addtitle><date>2012-08-30</date><risdate>2012</risdate><volume>488</volume><issue>7413</issue><spage>665</spage><epage>669</epage><pages>665-669</pages><issn>0028-0836</issn><eissn>1476-4687</eissn><coden>NATUAS</coden><abstract>In vivo
and
in vitro
studies show that the stem-cell E3 ubiquitin ligases RNF43 and ZNRF3 act as tumour suppressors in colorectal cancer models, and are involved in the negative regulation of the cancer-associated Wnt signalling pathway through limiting the cell-surface expression of Wnt receptors.
RNF43 protein in Wnt-linked colon cancer
Wnt signalling is critical for the function of intestinal stem cells; it also drives colorectal tumorigenesis. Bon-Kyoung Koo
et al
. find that two targets of Wnt signalling, the E3 ligases RNF43 and ZNFR3, are also important negative-feedback regulators of Wnt signalling. They act by limiting the cell-surface expression of Wnt receptors. Deletion of both genes in the mouse intestine leads to expansion of LGR5
+
intestinal stem cells and the development of adenomas. Furthermore, in human colon cancer cells, the expression of RNF43 reduces Wnt signalling. Mutated RNF43 has been found in human colorectal cancers, indicating that Wnt-pathway inhibitors that act at the level of Wnt secretion or Wnt-receptor activation may have therapeutic potential.
LGR5
+
stem cells reside at crypt bottoms, intermingled with Paneth cells that provide Wnt, Notch and epidermal growth factor signals
1
. Here we find that the related RNF43 and ZNRF3 transmembrane E3 ubiquitin ligases are uniquely expressed in LGR5
+
stem cells. Simultaneous deletion of the two genes encoding these proteins in the intestinal epithelium of mice induces rapidly growing adenomas containing high numbers of Paneth and LGR5
+
stem cells.
In vitro
, growth of organoids derived from these adenomas is arrested when Wnt secretion is inhibited, indicating a dependence of the adenoma stem cells on Wnt produced by adenoma Paneth cells. In the HEK293T human cancer cell line, expression of RNF43 blocks Wnt responses and targets surface-expressed frizzled receptors to lysosomes. In the
RNF43
-mutant colorectal cancer cell line HCT116, reconstitution of RNF43 expression removes its response to exogenous Wnt. We conclude that RNF43 and ZNRF3 reduce Wnt signals by selectively ubiquitinating frizzled receptors, thereby targeting these Wnt receptors for degradation.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>22895187</pmid><doi>10.1038/nature11308</doi><tpages>5</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0028-0836 |
| ispartof | Nature (London), 2012-08, Vol.488 (7413), p.665-669 |
| issn | 0028-0836 1476-4687 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1037661475 |
| source | MEDLINE; Nature; Springer Nature - Complete Springer Journals |
| subjects | 631/67/581 631/80/313/1461 631/80/86 Adenoma - metabolism Adenoma - pathology Animals beta Catenin - metabolism Biological and medical sciences Cell Proliferation Colorectal cancer Colorectal carcinoma Colorectal Neoplasms - metabolism Colorectal Neoplasms - pathology Development and progression DNA-Binding Proteins - deficiency DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Endocytosis Epidermal growth factor Frizzled Receptors - metabolism Gene expression HEK293 Cells Humanities and Social Sciences Humans Kinases letter Lysosomes - metabolism Medical sciences Mice multidisciplinary Multiple tumors. Solid tumors. Tumors in childhood (general aspects) Mutation Oncogene Proteins - deficiency Oncogene Proteins - genetics Oncogene Proteins - metabolism Organoids - cytology Organoids - metabolism Organoids - pathology Paneth Cells - metabolism Paneth Cells - pathology Physiological aspects Proteins Receptors, G-Protein-Coupled - genetics Receptors, G-Protein-Coupled - metabolism Receptors, Wnt - antagonists & inhibitors Receptors, Wnt - metabolism Risk factors Rodents Science Science (multidisciplinary) Stem cells Stem Cells - cytology Stem Cells - enzymology Stem Cells - metabolism Tumor Suppressor Proteins - deficiency Tumor Suppressor Proteins - genetics Tumor Suppressor Proteins - metabolism Tumors Ubiquitin Ubiquitin - metabolism Ubiquitin-Protein Ligases - deficiency Ubiquitin-Protein Ligases - genetics Ubiquitin-Protein Ligases - metabolism Ubiquitination Wnt Signaling Pathway - drug effects |
| title | Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors |
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