PI(4)P Promotes Phosphorylation and Conformational Change of Smoothened through Interaction with Its C-terminal Tail
In Hedgehog (Hh) signaling, binding of Hh to the Patched-Interference Hh (Ptc-Ihog) receptor complex relieves Ptc inhibition on Smoothened (Smo). A longstanding question is how Ptc inhibits Smo and how such inhibition is relieved by Hh stimulation. In this study, we found that Hh elevates production...
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| creator | Jiang, Kai Liu, Yajuan Fan, Junkai Zhang, Jie Li, Xiang-An Evers, B Mark Zhu, Haining Jia, Jianhang |
| description | In Hedgehog (Hh) signaling, binding of Hh to the Patched-Interference Hh (Ptc-Ihog) receptor complex relieves Ptc inhibition on Smoothened (Smo). A longstanding question is how Ptc inhibits Smo and how such inhibition is relieved by Hh stimulation. In this study, we found that Hh elevates production of phosphatidylinositol 4-phosphate (PI(4)P). Increased levels of PI(4)P promote, whereas decreased levels of PI(4)P inhibit, Hh signaling activity. We further found that PI(4)P directly binds Smo through an arginine motif, which then triggers Smo phosphorylation and activation. Moreover, we identified the pleckstrin homology (PH) domain of G protein-coupled receptor kinase 2 (Gprk2) as an essential component for enriching PI(4)P and facilitating Smo activation. PI(4)P also binds mouse Smo (mSmo) and promotes its phosphorylation and ciliary accumulation. Finally, Hh treatment increases the interaction between Smo and PI(4)P but decreases the interaction between Ptc and PI(4)P, indicating that, in addition to promoting PI(4)P production, Hh regulates the pool of PI(4)P associated with Ptc and Smo. |
| doi_str_mv | 10.1371/journal.pbio.1002375 |
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A longstanding question is how Ptc inhibits Smo and how such inhibition is relieved by Hh stimulation. In this study, we found that Hh elevates production of phosphatidylinositol 4-phosphate (PI(4)P). Increased levels of PI(4)P promote, whereas decreased levels of PI(4)P inhibit, Hh signaling activity. We further found that PI(4)P directly binds Smo through an arginine motif, which then triggers Smo phosphorylation and activation. Moreover, we identified the pleckstrin homology (PH) domain of G protein-coupled receptor kinase 2 (Gprk2) as an essential component for enriching PI(4)P and facilitating Smo activation. PI(4)P also binds mouse Smo (mSmo) and promotes its phosphorylation and ciliary accumulation. Finally, Hh treatment increases the interaction between Smo and PI(4)P but decreases the interaction between Ptc and PI(4)P, indicating that, in addition to promoting PI(4)P production, Hh regulates the pool of PI(4)P associated with Ptc and Smo.</description><identifier>ISSN: 1545-7885</identifier><identifier>ISSN: 1544-9173</identifier><identifier>EISSN: 1545-7885</identifier><identifier>DOI: 10.1371/journal.pbio.1002375</identifier><identifier>PMID: 26863604</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Biology and Life Sciences ; Cilia - metabolism ; Drosophila ; Drosophila Proteins - metabolism ; G-Protein-Coupled Receptor Kinase 2 - metabolism ; Hedgehog Proteins - metabolism ; Homeostasis ; Insects ; Kinases ; Localization ; Mice ; NIH 3T3 Cells ; Patched Receptors ; Patched-1 Receptor ; Phosphatidylinositol Phosphates - metabolism ; Phosphorylation ; Physical Sciences ; Proteins ; Receptors, Cell Surface - metabolism ; Receptors, G-Protein-Coupled - metabolism ; Research and Analysis Methods ; Rodents ; Signal transduction ; Smoothened Receptor</subject><ispartof>PLoS biology, 2016-02, Vol.14 (2), p.e1002375-e1002375</ispartof><rights>2016 Jiang et al 2016 Jiang et al</rights><rights>2016 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Jiang K, Liu Y, Fan J, Zhang J, Li X-A, Evers BM, et al. (2016) PI(4)P Promotes Phosphorylation and Conformational Change of Smoothened through Interaction with Its C-terminal Tail. PLoS Biol 14(2): e1002375. doi:10.1371/journal.pbio.1002375</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c498t-5937807c11ea6713ca8e5fe0d87eebc667400545d6b23b5bf5e9e7d0933a7843</citedby><cites>FETCH-LOGICAL-c498t-5937807c11ea6713ca8e5fe0d87eebc667400545d6b23b5bf5e9e7d0933a7843</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/PMC4749301/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4749301/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,724,777,781,861,882,2096,2915,23847,27905,27906,53772,53774,79349,79350</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26863604$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Nusse, Roel</contributor><creatorcontrib>Jiang, Kai</creatorcontrib><creatorcontrib>Liu, Yajuan</creatorcontrib><creatorcontrib>Fan, Junkai</creatorcontrib><creatorcontrib>Zhang, Jie</creatorcontrib><creatorcontrib>Li, Xiang-An</creatorcontrib><creatorcontrib>Evers, B Mark</creatorcontrib><creatorcontrib>Zhu, Haining</creatorcontrib><creatorcontrib>Jia, Jianhang</creatorcontrib><title>PI(4)P Promotes Phosphorylation and Conformational Change of Smoothened through Interaction with Its C-terminal Tail</title><title>PLoS biology</title><addtitle>PLoS Biol</addtitle><description>In Hedgehog (Hh) signaling, binding of Hh to the Patched-Interference Hh (Ptc-Ihog) receptor complex relieves Ptc inhibition on Smoothened (Smo). A longstanding question is how Ptc inhibits Smo and how such inhibition is relieved by Hh stimulation. In this study, we found that Hh elevates production of phosphatidylinositol 4-phosphate (PI(4)P). Increased levels of PI(4)P promote, whereas decreased levels of PI(4)P inhibit, Hh signaling activity. We further found that PI(4)P directly binds Smo through an arginine motif, which then triggers Smo phosphorylation and activation. Moreover, we identified the pleckstrin homology (PH) domain of G protein-coupled receptor kinase 2 (Gprk2) as an essential component for enriching PI(4)P and facilitating Smo activation. PI(4)P also binds mouse Smo (mSmo) and promotes its phosphorylation and ciliary accumulation. Finally, Hh treatment increases the interaction between Smo and PI(4)P but decreases the interaction between Ptc and PI(4)P, indicating that, in addition to promoting PI(4)P production, Hh regulates the pool of PI(4)P associated with Ptc and Smo.</description><subject>Animals</subject><subject>Biology and Life Sciences</subject><subject>Cilia - metabolism</subject><subject>Drosophila</subject><subject>Drosophila Proteins - metabolism</subject><subject>G-Protein-Coupled Receptor Kinase 2 - metabolism</subject><subject>Hedgehog Proteins - metabolism</subject><subject>Homeostasis</subject><subject>Insects</subject><subject>Kinases</subject><subject>Localization</subject><subject>Mice</subject><subject>NIH 3T3 Cells</subject><subject>Patched Receptors</subject><subject>Patched-1 Receptor</subject><subject>Phosphatidylinositol Phosphates - metabolism</subject><subject>Phosphorylation</subject><subject>Physical Sciences</subject><subject>Proteins</subject><subject>Receptors, Cell Surface - metabolism</subject><subject>Receptors, G-Protein-Coupled - metabolism</subject><subject>Research and Analysis Methods</subject><subject>Rodents</subject><subject>Signal transduction</subject><subject>Smoothened Receptor</subject><issn>1545-7885</issn><issn>1544-9173</issn><issn>1545-7885</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>DOA</sourceid><recordid>eNpVUk2P0zAUjBCIXRb-AYIcl0OLHduxc0FCER-VVqISvVuO89KkSvyK7YD23-O22dXuydZ4Zt48a7LsPSVryiT9fMDZOzOuj82Aa0pIwaR4kV1TwcVKKiVePrlfZW9COCROURXqdXZVlKpkJeHXWdxubvmnbb71OGGEkG97DMce_f1o4oAuN67Na3Qd-ukMmDGve-P2kGOX_54QYw8O2jz2Hud9n29cBG_sWftviAmIIa9XCZyGk3hnhvFt9qozY4B3y3mT7b5_29U_V3e_fmzqr3cryysVV6JiUhFpKQVTSsqsUSA6IK2SAI0tS8kJSSu2ZVOwRjSdgApkSyrGjFSc3WQfL7bHEYNe_itoKiWTJVeCJcbmwmjRHPTRD5Px9xrNoM8A-r02Pg52BE0sl6LtCmWo5IqnDAxs1yQvaCsQJHl9WabNzQStBRe9GZ-ZPn9xQ6_3-FdzyStGaDK4XQw8_pkhRD0NwcI4Ggc4n3KXglKRoicqv1CtxxA8dI9jKNGndjxsq0_t0Es7kuzD04iPooc6sP_o-Lod</recordid><startdate>20160201</startdate><enddate>20160201</enddate><creator>Jiang, Kai</creator><creator>Liu, Yajuan</creator><creator>Fan, Junkai</creator><creator>Zhang, Jie</creator><creator>Li, Xiang-An</creator><creator>Evers, B Mark</creator><creator>Zhu, Haining</creator><creator>Jia, Jianhang</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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><scope>DOA</scope><scope>CZG</scope></search><sort><creationdate>20160201</creationdate><title>PI(4)P Promotes Phosphorylation and Conformational Change of Smoothened through Interaction with Its C-terminal Tail</title><author>Jiang, Kai ; Liu, Yajuan ; Fan, Junkai ; Zhang, Jie ; Li, Xiang-An ; Evers, B Mark ; Zhu, Haining ; Jia, Jianhang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c498t-5937807c11ea6713ca8e5fe0d87eebc667400545d6b23b5bf5e9e7d0933a7843</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Animals</topic><topic>Biology and Life Sciences</topic><topic>Cilia - metabolism</topic><topic>Drosophila</topic><topic>Drosophila Proteins - metabolism</topic><topic>G-Protein-Coupled Receptor Kinase 2 - metabolism</topic><topic>Hedgehog Proteins - metabolism</topic><topic>Homeostasis</topic><topic>Insects</topic><topic>Kinases</topic><topic>Localization</topic><topic>Mice</topic><topic>NIH 3T3 Cells</topic><topic>Patched Receptors</topic><topic>Patched-1 Receptor</topic><topic>Phosphatidylinositol Phosphates - metabolism</topic><topic>Phosphorylation</topic><topic>Physical Sciences</topic><topic>Proteins</topic><topic>Receptors, Cell Surface - metabolism</topic><topic>Receptors, G-Protein-Coupled - metabolism</topic><topic>Research and Analysis Methods</topic><topic>Rodents</topic><topic>Signal transduction</topic><topic>Smoothened Receptor</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Jiang, Kai</creatorcontrib><creatorcontrib>Liu, Yajuan</creatorcontrib><creatorcontrib>Fan, Junkai</creatorcontrib><creatorcontrib>Zhang, Jie</creatorcontrib><creatorcontrib>Li, Xiang-An</creatorcontrib><creatorcontrib>Evers, B Mark</creatorcontrib><creatorcontrib>Zhu, Haining</creatorcontrib><creatorcontrib>Jia, Jianhang</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><collection>DOAJ Directory of Open Access Journals</collection><collection>PLoS Biology</collection><jtitle>PLoS biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Jiang, Kai</au><au>Liu, Yajuan</au><au>Fan, Junkai</au><au>Zhang, Jie</au><au>Li, Xiang-An</au><au>Evers, B Mark</au><au>Zhu, Haining</au><au>Jia, Jianhang</au><au>Nusse, Roel</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>PI(4)P Promotes Phosphorylation and Conformational Change of Smoothened through Interaction with Its C-terminal Tail</atitle><jtitle>PLoS biology</jtitle><addtitle>PLoS Biol</addtitle><date>2016-02-01</date><risdate>2016</risdate><volume>14</volume><issue>2</issue><spage>e1002375</spage><epage>e1002375</epage><pages>e1002375-e1002375</pages><issn>1545-7885</issn><issn>1544-9173</issn><eissn>1545-7885</eissn><abstract>In Hedgehog (Hh) signaling, binding of Hh to the Patched-Interference Hh (Ptc-Ihog) receptor complex relieves Ptc inhibition on Smoothened (Smo). A longstanding question is how Ptc inhibits Smo and how such inhibition is relieved by Hh stimulation. In this study, we found that Hh elevates production of phosphatidylinositol 4-phosphate (PI(4)P). Increased levels of PI(4)P promote, whereas decreased levels of PI(4)P inhibit, Hh signaling activity. We further found that PI(4)P directly binds Smo through an arginine motif, which then triggers Smo phosphorylation and activation. Moreover, we identified the pleckstrin homology (PH) domain of G protein-coupled receptor kinase 2 (Gprk2) as an essential component for enriching PI(4)P and facilitating Smo activation. PI(4)P also binds mouse Smo (mSmo) and promotes its phosphorylation and ciliary accumulation. Finally, Hh treatment increases the interaction between Smo and PI(4)P but decreases the interaction between Ptc and PI(4)P, indicating that, in addition to promoting PI(4)P production, Hh regulates the pool of PI(4)P associated with Ptc and Smo.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26863604</pmid><doi>10.1371/journal.pbio.1002375</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Biology and Life Sciences Cilia - metabolism Drosophila Drosophila Proteins - metabolism G-Protein-Coupled Receptor Kinase 2 - metabolism Hedgehog Proteins - metabolism Homeostasis Insects Kinases Localization Mice NIH 3T3 Cells Patched Receptors Patched-1 Receptor Phosphatidylinositol Phosphates - metabolism Phosphorylation Physical Sciences Proteins Receptors, Cell Surface - metabolism Receptors, G-Protein-Coupled - metabolism Research and Analysis Methods Rodents Signal transduction Smoothened Receptor |
| title | PI(4)P Promotes Phosphorylation and Conformational Change of Smoothened through Interaction with Its C-terminal Tail |
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