Phosphorylation of XIAP at threonine 180 controls its activity in Wnt signaling
X-linked inhibitor of apoptosis (XIAP) plays an important role in preventing apoptotic cell death. XIAP has been shown to participate in signaling pathways, including Wnt signaling. XIAP regulates Wnt signaling by promoting the monoubiquitylation of the co-repressor Groucho/TLE family proteins, decr...
Gespeichert in:
| Veröffentlicht in: | Journal of cell science 2018-05, Vol.131 (10), p.jcs210575-jcs210575 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | jcs210575 |
|---|---|
| container_issue | 10 |
| container_start_page | jcs210575 |
| container_title | Journal of cell science |
| container_volume | 131 |
| creator | Ng, Victoria H Hang, Brian I Sawyer, Leah M Neitzel, Leif R Crispi, Emily E Rose, Kristie L Popay, Tessa M Zhong, Alison Lee, Laura A Tansey, William P Huppert, Stacey Lee, Ethan |
| description | X-linked inhibitor of apoptosis (XIAP) plays an important role in preventing apoptotic cell death. XIAP has been shown to participate in signaling pathways, including Wnt signaling. XIAP regulates Wnt signaling by promoting the monoubiquitylation of the co-repressor Groucho/TLE family proteins, decreasing its affinity for the TCF/Lef family of transcription factors and allowing assembly of transcriptionally active β-catenin-TCF/Lef complexes. We now demonstrate that XIAP is phosphorylated by GSK3 at threonine 180, and that an alanine mutant (XIAP
) exhibits decreased Wnt activity compared to wild-type XIAP in cultured human cells and in
embryos. Although XIAP
ubiquitylates TLE3 at wild-type levels
, it exhibits a reduced capacity to ubiquitylate and bind TLE3 in human cells. XIAP
binds Smac (also known as DIABLO) and inhibits Fas-induced apoptosis to a similar degree to wild-type XIAP. Our studies uncover a new mechanism by which XIAP is specifically directed towards a Wnt signaling function versus its anti-apoptotic function. These findings have implications for development of anti-XIAP therapeutics for human cancers. |
| doi_str_mv | 10.1242/jcs.210575 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6031333</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2049879445</sourcerecordid><originalsourceid>FETCH-LOGICAL-c406t-4c6ebc2b1302f98a3f599c3d19b206c710f69b108d5defe62ae18db215438a8a3</originalsourceid><addsrcrecordid>eNpdkcFqGzEQhkVpaFynlz5AEfRSApuMpNVKuhRCaFpDID4kpDeh1WptmbXkSnLAb58Ndk2SucxhPn7-4UPoK4ELQmt6ubL5ghLggn9AE1ILUSnCxEc0AaCkUpyxU_Q55xUACKrEJ3RKVSOkAj5Bd_NlzJtlTLvBFB8Djj3-O7uaY1NwWSYXgw8OEwnYxlBSHDL2JWNji3_yZYd9wI-h4OwXwQw-LM7QSW-G7L4c9hQ93Py6v_5T3d79nl1f3Va2hqZUtW1ca2lLGNBeScN6rpRlHVEthcYKAn2jWgKy453rXUONI7JrKeE1k2bkp-jnPnezbdeus24sZwa9SX5t0k5H4_XbS_BLvYhPugFG2DhT9OMQkOK_rctFr322bhhMcHGbNQUqFZd79Ps7dBW3afz3haqVFKqu-Uid7ymbYs7J9ccyBPSLJz160ntPI_ztdf0j-l8MewbHi44S</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2049879445</pqid></control><display><type>article</type><title>Phosphorylation of XIAP at threonine 180 controls its activity in Wnt signaling</title><source>EZB-FREE-00999 freely available EZB journals</source><source>Alma/SFX Local Collection</source><source>Company of Biologists</source><creator>Ng, Victoria H ; Hang, Brian I ; Sawyer, Leah M ; Neitzel, Leif R ; Crispi, Emily E ; Rose, Kristie L ; Popay, Tessa M ; Zhong, Alison ; Lee, Laura A ; Tansey, William P ; Huppert, Stacey ; Lee, Ethan</creator><creatorcontrib>Ng, Victoria H ; Hang, Brian I ; Sawyer, Leah M ; Neitzel, Leif R ; Crispi, Emily E ; Rose, Kristie L ; Popay, Tessa M ; Zhong, Alison ; Lee, Laura A ; Tansey, William P ; Huppert, Stacey ; Lee, Ethan</creatorcontrib><description>X-linked inhibitor of apoptosis (XIAP) plays an important role in preventing apoptotic cell death. XIAP has been shown to participate in signaling pathways, including Wnt signaling. XIAP regulates Wnt signaling by promoting the monoubiquitylation of the co-repressor Groucho/TLE family proteins, decreasing its affinity for the TCF/Lef family of transcription factors and allowing assembly of transcriptionally active β-catenin-TCF/Lef complexes. We now demonstrate that XIAP is phosphorylated by GSK3 at threonine 180, and that an alanine mutant (XIAP
) exhibits decreased Wnt activity compared to wild-type XIAP in cultured human cells and in
embryos. Although XIAP
ubiquitylates TLE3 at wild-type levels
, it exhibits a reduced capacity to ubiquitylate and bind TLE3 in human cells. XIAP
binds Smac (also known as DIABLO) and inhibits Fas-induced apoptosis to a similar degree to wild-type XIAP. Our studies uncover a new mechanism by which XIAP is specifically directed towards a Wnt signaling function versus its anti-apoptotic function. These findings have implications for development of anti-XIAP therapeutics for human cancers.</description><identifier>ISSN: 0021-9533</identifier><identifier>EISSN: 1477-9137</identifier><identifier>DOI: 10.1242/jcs.210575</identifier><identifier>PMID: 29678905</identifier><language>eng</language><publisher>England: The Company of Biologists Ltd</publisher><subject>Alanine ; Apoptosis ; Cell death ; DIABLO protein ; Drug development ; Embryos ; Heparan sulfate ; LEF protein ; Phosphorylation ; Proteins ; Short Report ; Signaling ; Threonine ; Transcription factors ; Wnt protein ; XIAP protein ; β-catenin</subject><ispartof>Journal of cell science, 2018-05, Vol.131 (10), p.jcs210575-jcs210575</ispartof><rights>2018. Published by The Company of Biologists Ltd.</rights><rights>Copyright The Company of Biologists Ltd May 15, 2018</rights><rights>2018. Published by The Company of Biologists Ltd 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c406t-4c6ebc2b1302f98a3f599c3d19b206c710f69b108d5defe62ae18db215438a8a3</citedby><cites>FETCH-LOGICAL-c406t-4c6ebc2b1302f98a3f599c3d19b206c710f69b108d5defe62ae18db215438a8a3</cites><orcidid>0000-0003-4591-4466 ; 0000-0003-4868-7406 ; 0000-0001-8405-6156 ; 0000-0003-2344-8468</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,3678,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29678905$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ng, Victoria H</creatorcontrib><creatorcontrib>Hang, Brian I</creatorcontrib><creatorcontrib>Sawyer, Leah M</creatorcontrib><creatorcontrib>Neitzel, Leif R</creatorcontrib><creatorcontrib>Crispi, Emily E</creatorcontrib><creatorcontrib>Rose, Kristie L</creatorcontrib><creatorcontrib>Popay, Tessa M</creatorcontrib><creatorcontrib>Zhong, Alison</creatorcontrib><creatorcontrib>Lee, Laura A</creatorcontrib><creatorcontrib>Tansey, William P</creatorcontrib><creatorcontrib>Huppert, Stacey</creatorcontrib><creatorcontrib>Lee, Ethan</creatorcontrib><title>Phosphorylation of XIAP at threonine 180 controls its activity in Wnt signaling</title><title>Journal of cell science</title><addtitle>J Cell Sci</addtitle><description>X-linked inhibitor of apoptosis (XIAP) plays an important role in preventing apoptotic cell death. XIAP has been shown to participate in signaling pathways, including Wnt signaling. XIAP regulates Wnt signaling by promoting the monoubiquitylation of the co-repressor Groucho/TLE family proteins, decreasing its affinity for the TCF/Lef family of transcription factors and allowing assembly of transcriptionally active β-catenin-TCF/Lef complexes. We now demonstrate that XIAP is phosphorylated by GSK3 at threonine 180, and that an alanine mutant (XIAP
) exhibits decreased Wnt activity compared to wild-type XIAP in cultured human cells and in
embryos. Although XIAP
ubiquitylates TLE3 at wild-type levels
, it exhibits a reduced capacity to ubiquitylate and bind TLE3 in human cells. XIAP
binds Smac (also known as DIABLO) and inhibits Fas-induced apoptosis to a similar degree to wild-type XIAP. Our studies uncover a new mechanism by which XIAP is specifically directed towards a Wnt signaling function versus its anti-apoptotic function. These findings have implications for development of anti-XIAP therapeutics for human cancers.</description><subject>Alanine</subject><subject>Apoptosis</subject><subject>Cell death</subject><subject>DIABLO protein</subject><subject>Drug development</subject><subject>Embryos</subject><subject>Heparan sulfate</subject><subject>LEF protein</subject><subject>Phosphorylation</subject><subject>Proteins</subject><subject>Short Report</subject><subject>Signaling</subject><subject>Threonine</subject><subject>Transcription factors</subject><subject>Wnt protein</subject><subject>XIAP protein</subject><subject>β-catenin</subject><issn>0021-9533</issn><issn>1477-9137</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><recordid>eNpdkcFqGzEQhkVpaFynlz5AEfRSApuMpNVKuhRCaFpDID4kpDeh1WptmbXkSnLAb58Ndk2SucxhPn7-4UPoK4ELQmt6ubL5ghLggn9AE1ILUSnCxEc0AaCkUpyxU_Q55xUACKrEJ3RKVSOkAj5Bd_NlzJtlTLvBFB8Djj3-O7uaY1NwWSYXgw8OEwnYxlBSHDL2JWNji3_yZYd9wI-h4OwXwQw-LM7QSW-G7L4c9hQ93Py6v_5T3d79nl1f3Va2hqZUtW1ca2lLGNBeScN6rpRlHVEthcYKAn2jWgKy453rXUONI7JrKeE1k2bkp-jnPnezbdeus24sZwa9SX5t0k5H4_XbS_BLvYhPugFG2DhT9OMQkOK_rctFr322bhhMcHGbNQUqFZd79Ps7dBW3afz3haqVFKqu-Uid7ymbYs7J9ccyBPSLJz160ntPI_ztdf0j-l8MewbHi44S</recordid><startdate>20180515</startdate><enddate>20180515</enddate><creator>Ng, Victoria H</creator><creator>Hang, Brian I</creator><creator>Sawyer, Leah M</creator><creator>Neitzel, Leif R</creator><creator>Crispi, Emily E</creator><creator>Rose, Kristie L</creator><creator>Popay, Tessa M</creator><creator>Zhong, Alison</creator><creator>Lee, Laura A</creator><creator>Tansey, William P</creator><creator>Huppert, Stacey</creator><creator>Lee, Ethan</creator><general>The Company of Biologists Ltd</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-4591-4466</orcidid><orcidid>https://orcid.org/0000-0003-4868-7406</orcidid><orcidid>https://orcid.org/0000-0001-8405-6156</orcidid><orcidid>https://orcid.org/0000-0003-2344-8468</orcidid></search><sort><creationdate>20180515</creationdate><title>Phosphorylation of XIAP at threonine 180 controls its activity in Wnt signaling</title><author>Ng, Victoria H ; Hang, Brian I ; Sawyer, Leah M ; Neitzel, Leif R ; Crispi, Emily E ; Rose, Kristie L ; Popay, Tessa M ; Zhong, Alison ; Lee, Laura A ; Tansey, William P ; Huppert, Stacey ; Lee, Ethan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c406t-4c6ebc2b1302f98a3f599c3d19b206c710f69b108d5defe62ae18db215438a8a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Alanine</topic><topic>Apoptosis</topic><topic>Cell death</topic><topic>DIABLO protein</topic><topic>Drug development</topic><topic>Embryos</topic><topic>Heparan sulfate</topic><topic>LEF protein</topic><topic>Phosphorylation</topic><topic>Proteins</topic><topic>Short Report</topic><topic>Signaling</topic><topic>Threonine</topic><topic>Transcription factors</topic><topic>Wnt protein</topic><topic>XIAP protein</topic><topic>β-catenin</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ng, Victoria H</creatorcontrib><creatorcontrib>Hang, Brian I</creatorcontrib><creatorcontrib>Sawyer, Leah M</creatorcontrib><creatorcontrib>Neitzel, Leif R</creatorcontrib><creatorcontrib>Crispi, Emily E</creatorcontrib><creatorcontrib>Rose, Kristie L</creatorcontrib><creatorcontrib>Popay, Tessa M</creatorcontrib><creatorcontrib>Zhong, Alison</creatorcontrib><creatorcontrib>Lee, Laura A</creatorcontrib><creatorcontrib>Tansey, William P</creatorcontrib><creatorcontrib>Huppert, Stacey</creatorcontrib><creatorcontrib>Lee, Ethan</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of cell science</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ng, Victoria H</au><au>Hang, Brian I</au><au>Sawyer, Leah M</au><au>Neitzel, Leif R</au><au>Crispi, Emily E</au><au>Rose, Kristie L</au><au>Popay, Tessa M</au><au>Zhong, Alison</au><au>Lee, Laura A</au><au>Tansey, William P</au><au>Huppert, Stacey</au><au>Lee, Ethan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Phosphorylation of XIAP at threonine 180 controls its activity in Wnt signaling</atitle><jtitle>Journal of cell science</jtitle><addtitle>J Cell Sci</addtitle><date>2018-05-15</date><risdate>2018</risdate><volume>131</volume><issue>10</issue><spage>jcs210575</spage><epage>jcs210575</epage><pages>jcs210575-jcs210575</pages><issn>0021-9533</issn><eissn>1477-9137</eissn><abstract>X-linked inhibitor of apoptosis (XIAP) plays an important role in preventing apoptotic cell death. XIAP has been shown to participate in signaling pathways, including Wnt signaling. XIAP regulates Wnt signaling by promoting the monoubiquitylation of the co-repressor Groucho/TLE family proteins, decreasing its affinity for the TCF/Lef family of transcription factors and allowing assembly of transcriptionally active β-catenin-TCF/Lef complexes. We now demonstrate that XIAP is phosphorylated by GSK3 at threonine 180, and that an alanine mutant (XIAP
) exhibits decreased Wnt activity compared to wild-type XIAP in cultured human cells and in
embryos. Although XIAP
ubiquitylates TLE3 at wild-type levels
, it exhibits a reduced capacity to ubiquitylate and bind TLE3 in human cells. XIAP
binds Smac (also known as DIABLO) and inhibits Fas-induced apoptosis to a similar degree to wild-type XIAP. Our studies uncover a new mechanism by which XIAP is specifically directed towards a Wnt signaling function versus its anti-apoptotic function. These findings have implications for development of anti-XIAP therapeutics for human cancers.</abstract><cop>England</cop><pub>The Company of Biologists Ltd</pub><pmid>29678905</pmid><doi>10.1242/jcs.210575</doi><orcidid>https://orcid.org/0000-0003-4591-4466</orcidid><orcidid>https://orcid.org/0000-0003-4868-7406</orcidid><orcidid>https://orcid.org/0000-0001-8405-6156</orcidid><orcidid>https://orcid.org/0000-0003-2344-8468</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0021-9533 |
| ispartof | Journal of cell science, 2018-05, Vol.131 (10), p.jcs210575-jcs210575 |
| issn | 0021-9533 1477-9137 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6031333 |
| source | EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection; Company of Biologists |
| subjects | Alanine Apoptosis Cell death DIABLO protein Drug development Embryos Heparan sulfate LEF protein Phosphorylation Proteins Short Report Signaling Threonine Transcription factors Wnt protein XIAP protein β-catenin |
| title | Phosphorylation of XIAP at threonine 180 controls its activity in Wnt signaling |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-24T06%3A10%3A55IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Phosphorylation%20of%20XIAP%20at%20threonine%20180%20controls%20its%20activity%20in%20Wnt%20signaling&rft.jtitle=Journal%20of%20cell%20science&rft.au=Ng,%20Victoria%20H&rft.date=2018-05-15&rft.volume=131&rft.issue=10&rft.spage=jcs210575&rft.epage=jcs210575&rft.pages=jcs210575-jcs210575&rft.issn=0021-9533&rft.eissn=1477-9137&rft_id=info:doi/10.1242/jcs.210575&rft_dat=%3Cproquest_pubme%3E2049879445%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2049879445&rft_id=info:pmid/29678905&rfr_iscdi=true |