Self-association of the APC tumor suppressor is required for the assembly, stability, and activity of the Wnt signaling destruction complex
The tumor suppressor adenomatous polyposis coli (APC) is an essential negative regulator of Wnt signaling through its activity in the destruction complex with Axin, GSK3β, and CK1 that targets β-catenin/Armadillo (β-cat/Arm) for proteosomal degradation. The destruction complex forms macromolecular p...
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| Veröffentlicht in: | Molecular biology of the cell 2014-11, Vol.25 (21), p.3424-3436 |
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| creator | Kunttas-Tatli, Ezgi Roberts, David M McCartney, Brooke M |
| description | The tumor suppressor adenomatous polyposis coli (APC) is an essential negative regulator of Wnt signaling through its activity in the destruction complex with Axin, GSK3β, and CK1 that targets β-catenin/Armadillo (β-cat/Arm) for proteosomal degradation. The destruction complex forms macromolecular particles we termed the destructosome. Whereas APC functions in the complex through its ability to bind both β-cat and Axin, we hypothesize that APC proteins play an additional role in destructosome assembly through self-association. Here we show that a novel N-terminal coil, the APC self-association domain (ASAD), found in vertebrate and invertebrate APCs, directly mediates self-association of Drosophila APC2 and plays an essential role in the assembly and stability of the destructosome that regulates β-cat degradation in Drosophila and human cells. Consistent with this, removal of the ASAD from the Drosophila embryo results in β-cat/Arm accumulation and aberrant Wnt pathway activation. These results suggest that APC proteins are required not only for the activity of the destructosome, but also for the assembly and stability of this macromolecular machine. |
| doi_str_mv | 10.1091/mbc.E14-04-0885 |
| format | Article |
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The destruction complex forms macromolecular particles we termed the destructosome. Whereas APC functions in the complex through its ability to bind both β-cat and Axin, we hypothesize that APC proteins play an additional role in destructosome assembly through self-association. Here we show that a novel N-terminal coil, the APC self-association domain (ASAD), found in vertebrate and invertebrate APCs, directly mediates self-association of Drosophila APC2 and plays an essential role in the assembly and stability of the destructosome that regulates β-cat degradation in Drosophila and human cells. Consistent with this, removal of the ASAD from the Drosophila embryo results in β-cat/Arm accumulation and aberrant Wnt pathway activation. 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This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).</rights><rights>2014 Kunttas-Tatli This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License ( ). 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c439t-a40b013f7914a104d85b98162e1bc335668067a883868d59043cca11c85ef9b33</citedby><cites>FETCH-LOGICAL-c439t-a40b013f7914a104d85b98162e1bc335668067a883868d59043cca11c85ef9b33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214788/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214788/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25208568$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Fehon, Richard</contributor><creatorcontrib>Kunttas-Tatli, Ezgi</creatorcontrib><creatorcontrib>Roberts, David M</creatorcontrib><creatorcontrib>McCartney, Brooke M</creatorcontrib><title>Self-association of the APC tumor suppressor is required for the assembly, stability, and activity of the Wnt signaling destruction complex</title><title>Molecular biology of the cell</title><addtitle>Mol Biol Cell</addtitle><description>The tumor suppressor adenomatous polyposis coli (APC) is an essential negative regulator of Wnt signaling through its activity in the destruction complex with Axin, GSK3β, and CK1 that targets β-catenin/Armadillo (β-cat/Arm) for proteosomal degradation. The destruction complex forms macromolecular particles we termed the destructosome. Whereas APC functions in the complex through its ability to bind both β-cat and Axin, we hypothesize that APC proteins play an additional role in destructosome assembly through self-association. Here we show that a novel N-terminal coil, the APC self-association domain (ASAD), found in vertebrate and invertebrate APCs, directly mediates self-association of Drosophila APC2 and plays an essential role in the assembly and stability of the destructosome that regulates β-cat degradation in Drosophila and human cells. Consistent with this, removal of the ASAD from the Drosophila embryo results in β-cat/Arm accumulation and aberrant Wnt pathway activation. These results suggest that APC proteins are required not only for the activity of the destructosome, but also for the assembly and stability of this macromolecular machine.</description><subject>Adenomatous Polyposis Coli Protein - chemistry</subject><subject>Adenomatous Polyposis Coli Protein - metabolism</subject><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Animals, Genetically Modified</subject><subject>Armadillo Domain Proteins - genetics</subject><subject>Armadillo Domain Proteins - metabolism</subject><subject>Axin Protein - genetics</subject><subject>Axin Protein - metabolism</subject><subject>beta Catenin - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Colorectal Neoplasms - metabolism</subject><subject>Colorectal Neoplasms - pathology</subject><subject>Drosophila - embryology</subject><subject>Drosophila - genetics</subject><subject>Drosophila - metabolism</subject><subject>Drosophila Proteins - genetics</subject><subject>Drosophila Proteins - metabolism</subject><subject>Embryo, Nonmammalian - cytology</subject><subject>Humans</subject><subject>Molecular Sequence Data</subject><subject>Protein Structure, Tertiary</subject><subject>Transcription Factors - genetics</subject><subject>Transcription Factors - metabolism</subject><subject>Tumor Suppressor Proteins - genetics</subject><subject>Tumor Suppressor Proteins - metabolism</subject><subject>Wnt Signaling Pathway</subject><issn>1059-1524</issn><issn>1939-4586</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkU1LHTEUhkNpqfbatTvJsouO5kw-brIR5GJbQWihSpchk8lcI5nJmGREf4N_uvGTFg7kHPKe9014ENoHcghEwdHY2cNTYA2pJSV_h3ZBUdUwLsX72hOuGuAt20Gfcr4mBBgT649op-UtkVzIXfTw24WhMTlH603xccJxwOXK4ZNfG1yWMSacl3lOrioS9hknd7P45Ho81PlRWHfd2IX7rzgX0_ngS23N1GNji7-t06vjn6ng7LeTCX7a4t7lkhb7FGnjOAd3t4c-DCZk9_nlXKHLb6cXmx_N-c_vZ5uT88YyqkpjGOkI0GGtgBkgrJe8UxJE66CzlHIhJBFrIyWVQvZcEUatNQBWcjeojtIVOn72nZdudL11U0km6Dn50aR7HY3X_99M_kpv461mLbB19V2hLy8GKd4s9SN69Nm6EMzk4pI1iEoBVI2u0qNnqU0x5-SGtxgg-hGhrgi1A6ZJrYqwbhz8-7o3_Ssz-hdRPJrP</recordid><startdate>20141101</startdate><enddate>20141101</enddate><creator>Kunttas-Tatli, Ezgi</creator><creator>Roberts, David M</creator><creator>McCartney, Brooke M</creator><general>The American Society for Cell Biology</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20141101</creationdate><title>Self-association of the APC tumor suppressor is required for the assembly, stability, and activity of the Wnt signaling destruction complex</title><author>Kunttas-Tatli, Ezgi ; Roberts, David M ; McCartney, Brooke M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c439t-a40b013f7914a104d85b98162e1bc335668067a883868d59043cca11c85ef9b33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Adenomatous Polyposis Coli Protein - chemistry</topic><topic>Adenomatous Polyposis Coli Protein - metabolism</topic><topic>Amino Acid Sequence</topic><topic>Animals</topic><topic>Animals, Genetically Modified</topic><topic>Armadillo Domain Proteins - genetics</topic><topic>Armadillo Domain Proteins - metabolism</topic><topic>Axin Protein - genetics</topic><topic>Axin Protein - metabolism</topic><topic>beta Catenin - metabolism</topic><topic>Cell Line, Tumor</topic><topic>Colorectal Neoplasms - metabolism</topic><topic>Colorectal Neoplasms - pathology</topic><topic>Drosophila - embryology</topic><topic>Drosophila - genetics</topic><topic>Drosophila - metabolism</topic><topic>Drosophila Proteins - genetics</topic><topic>Drosophila Proteins - metabolism</topic><topic>Embryo, Nonmammalian - cytology</topic><topic>Humans</topic><topic>Molecular Sequence Data</topic><topic>Protein Structure, Tertiary</topic><topic>Transcription Factors - genetics</topic><topic>Transcription Factors - metabolism</topic><topic>Tumor Suppressor Proteins - genetics</topic><topic>Tumor Suppressor Proteins - metabolism</topic><topic>Wnt Signaling Pathway</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kunttas-Tatli, Ezgi</creatorcontrib><creatorcontrib>Roberts, David M</creatorcontrib><creatorcontrib>McCartney, Brooke M</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular biology of the cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kunttas-Tatli, Ezgi</au><au>Roberts, David M</au><au>McCartney, Brooke M</au><au>Fehon, Richard</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Self-association of the APC tumor suppressor is required for the assembly, stability, and activity of the Wnt signaling destruction complex</atitle><jtitle>Molecular biology of the cell</jtitle><addtitle>Mol Biol Cell</addtitle><date>2014-11-01</date><risdate>2014</risdate><volume>25</volume><issue>21</issue><spage>3424</spage><epage>3436</epage><pages>3424-3436</pages><issn>1059-1524</issn><eissn>1939-4586</eissn><abstract>The tumor suppressor adenomatous polyposis coli (APC) is an essential negative regulator of Wnt signaling through its activity in the destruction complex with Axin, GSK3β, and CK1 that targets β-catenin/Armadillo (β-cat/Arm) for proteosomal degradation. The destruction complex forms macromolecular particles we termed the destructosome. Whereas APC functions in the complex through its ability to bind both β-cat and Axin, we hypothesize that APC proteins play an additional role in destructosome assembly through self-association. Here we show that a novel N-terminal coil, the APC self-association domain (ASAD), found in vertebrate and invertebrate APCs, directly mediates self-association of Drosophila APC2 and plays an essential role in the assembly and stability of the destructosome that regulates β-cat degradation in Drosophila and human cells. Consistent with this, removal of the ASAD from the Drosophila embryo results in β-cat/Arm accumulation and aberrant Wnt pathway activation. 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| subjects | Adenomatous Polyposis Coli Protein - chemistry Adenomatous Polyposis Coli Protein - metabolism Amino Acid Sequence Animals Animals, Genetically Modified Armadillo Domain Proteins - genetics Armadillo Domain Proteins - metabolism Axin Protein - genetics Axin Protein - metabolism beta Catenin - metabolism Cell Line, Tumor Colorectal Neoplasms - metabolism Colorectal Neoplasms - pathology Drosophila - embryology Drosophila - genetics Drosophila - metabolism Drosophila Proteins - genetics Drosophila Proteins - metabolism Embryo, Nonmammalian - cytology Humans Molecular Sequence Data Protein Structure, Tertiary Transcription Factors - genetics Transcription Factors - metabolism Tumor Suppressor Proteins - genetics Tumor Suppressor Proteins - metabolism Wnt Signaling Pathway |
| title | Self-association of the APC tumor suppressor is required for the assembly, stability, and activity of the Wnt signaling destruction complex |
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