Minibrain and Wings apart control organ growth and tissue patterning through down-regulation of Capicua
The transcriptional repressor Capicua (Cic) controls tissue patterning and restricts organ growth, and has been recently implicated in several cancers. Cic has emerged as a primary sensor of signaling downstream of the receptor tyrosine kinase (RTK)/extracellular signal-regulated kinase (ERK) pathwa...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2016-09, Vol.113 (38), p.10583-10588 |
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| creator | Yang, Liu Paul, Sayantanee Trieu, Kenneth G. Dent, Lucas G. Froldi, Francesca Forés, Marta Webster, Kaitlyn Siegfried, Kellee R. Kondo, Shu Harvey, Kieran Cheng, Louise Jiménez, Gerardo Shvartsman, Stanislav Y. Veraksa, Alexey |
| description | The transcriptional repressor Capicua (Cic) controls tissue patterning and restricts organ growth, and has been recently implicated in several cancers. Cic has emerged as a primary sensor of signaling downstream of the receptor tyrosine kinase (RTK)/extracellular signal-regulated kinase (ERK) pathway, but how Cic activity is regulated in different cellular contexts remains poorly understood. We found that the kinase Minibrain (Mnb, ortholog of mammalian DYRK1A), acting through the adaptor protein Wings apart (Wap), physically interacts with and phosphorylates the Cic protein. Mnb and Wap inhibit Cic function by limiting its transcriptional repressor activity. Down-regulation of Cic by Mnb/Wap is necessary for promoting the growth of multiple organs, including the wings, eyes, and the brain, and for proper tissue patterning in the wing. We have thus uncovered a previously unknown mechanism of down-regulation of Cic activity by Mnb and Wap, which operates independently from the ERK-mediated control of Cic. Therefore, Cic functions as an integrator of upstream signals that are essential for tissue patterning and organ growth. Finally, because DYRK1A and CIC exhibit, respectively, prooncogenic vs. tumor suppressor activities in human oligodendroglioma, our results raise the possibility that DYRK1A may also down-regulate CIC in human cells. |
| doi_str_mv | 10.1073/pnas.1609417113 |
| format | Article |
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Cic has emerged as a primary sensor of signaling downstream of the receptor tyrosine kinase (RTK)/extracellular signal-regulated kinase (ERK) pathway, but how Cic activity is regulated in different cellular contexts remains poorly understood. We found that the kinase Minibrain (Mnb, ortholog of mammalian DYRK1A), acting through the adaptor protein Wings apart (Wap), physically interacts with and phosphorylates the Cic protein. Mnb and Wap inhibit Cic function by limiting its transcriptional repressor activity. Down-regulation of Cic by Mnb/Wap is necessary for promoting the growth of multiple organs, including the wings, eyes, and the brain, and for proper tissue patterning in the wing. We have thus uncovered a previously unknown mechanism of down-regulation of Cic activity by Mnb and Wap, which operates independently from the ERK-mediated control of Cic. Therefore, Cic functions as an integrator of upstream signals that are essential for tissue patterning and organ growth. Finally, because DYRK1A and CIC exhibit, respectively, prooncogenic vs. tumor suppressor activities in human oligodendroglioma, our results raise the possibility that DYRK1A may also down-regulate CIC in human cells.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1609417113</identifier><identifier>PMID: 27601662</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Adaptor Proteins, Signal Transducing - genetics ; Animals ; Biological Sciences ; Biosensors ; Body Patterning - genetics ; Cancer ; Drosophila - genetics ; Drosophila - growth & development ; Drosophila Proteins - biosynthesis ; Drosophila Proteins - genetics ; Dyrk Kinases ; Gene Expression Regulation, Developmental ; HMGB Proteins - biosynthesis ; HMGB Proteins - genetics ; Humans ; Kinases ; Neoplasms - genetics ; Phosphorylation ; Protein Serine-Threonine Kinases - biosynthesis ; Protein Serine-Threonine Kinases - genetics ; Protein-Tyrosine Kinases - genetics ; Proteins ; Repressor Proteins - biosynthesis ; Repressor Proteins - genetics ; Tissues ; Wings, Animal - growth & development</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2016-09, Vol.113 (38), p.10583-10588</ispartof><rights>Volumes 1–89 and 106–113, copyright as a collective work only; author(s) retains copyright to individual articles</rights><rights>Copyright National Academy of Sciences Sep 20, 2016</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c509t-e402cbe263664e8f24466d320561573fcbd8fb2ae3e04aaa6b22b0d10ddef6613</citedby><cites>FETCH-LOGICAL-c509t-e402cbe263664e8f24466d320561573fcbd8fb2ae3e04aaa6b22b0d10ddef6613</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/26471632$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/26471632$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,727,780,784,803,885,27923,27924,53790,53792,58016,58249</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27601662$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yang, Liu</creatorcontrib><creatorcontrib>Paul, Sayantanee</creatorcontrib><creatorcontrib>Trieu, Kenneth G.</creatorcontrib><creatorcontrib>Dent, Lucas G.</creatorcontrib><creatorcontrib>Froldi, Francesca</creatorcontrib><creatorcontrib>Forés, Marta</creatorcontrib><creatorcontrib>Webster, Kaitlyn</creatorcontrib><creatorcontrib>Siegfried, Kellee R.</creatorcontrib><creatorcontrib>Kondo, Shu</creatorcontrib><creatorcontrib>Harvey, Kieran</creatorcontrib><creatorcontrib>Cheng, Louise</creatorcontrib><creatorcontrib>Jiménez, Gerardo</creatorcontrib><creatorcontrib>Shvartsman, Stanislav Y.</creatorcontrib><creatorcontrib>Veraksa, Alexey</creatorcontrib><title>Minibrain and Wings apart control organ growth and tissue patterning through down-regulation of Capicua</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>The transcriptional repressor Capicua (Cic) controls tissue patterning and restricts organ growth, and has been recently implicated in several cancers. Cic has emerged as a primary sensor of signaling downstream of the receptor tyrosine kinase (RTK)/extracellular signal-regulated kinase (ERK) pathway, but how Cic activity is regulated in different cellular contexts remains poorly understood. We found that the kinase Minibrain (Mnb, ortholog of mammalian DYRK1A), acting through the adaptor protein Wings apart (Wap), physically interacts with and phosphorylates the Cic protein. Mnb and Wap inhibit Cic function by limiting its transcriptional repressor activity. Down-regulation of Cic by Mnb/Wap is necessary for promoting the growth of multiple organs, including the wings, eyes, and the brain, and for proper tissue patterning in the wing. We have thus uncovered a previously unknown mechanism of down-regulation of Cic activity by Mnb and Wap, which operates independently from the ERK-mediated control of Cic. Therefore, Cic functions as an integrator of upstream signals that are essential for tissue patterning and organ growth. Finally, because DYRK1A and CIC exhibit, respectively, prooncogenic vs. tumor suppressor activities in human oligodendroglioma, our results raise the possibility that DYRK1A may also down-regulate CIC in human cells.</description><subject>Adaptor Proteins, Signal Transducing - genetics</subject><subject>Animals</subject><subject>Biological Sciences</subject><subject>Biosensors</subject><subject>Body Patterning - genetics</subject><subject>Cancer</subject><subject>Drosophila - genetics</subject><subject>Drosophila - growth & development</subject><subject>Drosophila Proteins - biosynthesis</subject><subject>Drosophila Proteins - genetics</subject><subject>Dyrk Kinases</subject><subject>Gene Expression Regulation, Developmental</subject><subject>HMGB Proteins - biosynthesis</subject><subject>HMGB Proteins - genetics</subject><subject>Humans</subject><subject>Kinases</subject><subject>Neoplasms - genetics</subject><subject>Phosphorylation</subject><subject>Protein Serine-Threonine Kinases - biosynthesis</subject><subject>Protein Serine-Threonine Kinases - genetics</subject><subject>Protein-Tyrosine Kinases - genetics</subject><subject>Proteins</subject><subject>Repressor Proteins - biosynthesis</subject><subject>Repressor Proteins - genetics</subject><subject>Tissues</subject><subject>Wings, Animal - growth & development</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkc1v1DAQxa0KRJfCuSeQpV64pB1_xEkulaoVX1IRl1YcrUniZL3K2qnttOK_x8uWFjjNYX7vzTw9Qk4ZnDOoxMXsMJ4zBY1kFWPiiKwYNKxQsoEXZAXAq6KWXB6T1zFuAaApa3hFjnmlgCnFV2T8Zp1tA1pH0fX0h3VjpDhjSLTzLgU_UR9GdHQM_iFtfkPJxrgYOmNKJrisoGkT_DJuaO8fXBHMuEyYrHfUD3SNs-0WfENeDjhF8_ZxnpDbTx9v1l-K6--fv66vrouuhCYVRgLvWsOVUEqaeuBSKtULDqViZSWGru3roeVohAGJiKrlvIWeQd-bQSkmTsjlwXde2p3pO5Mz4KTnYHcYfmqPVv-7cXajR3-vSxBlXVXZ4MOjQfB3i4lJ72zszDShM36JmtWc558Y7G-d_Ydu_RJcjrenSikaIXimLg5UF3yMwQxPzzDQ-xL1vkT9XGJWvP87wxP_p7UMvDsA25h8eN4rWTGVT_4Cq9ekLQ</recordid><startdate>20160920</startdate><enddate>20160920</enddate><creator>Yang, Liu</creator><creator>Paul, Sayantanee</creator><creator>Trieu, Kenneth G.</creator><creator>Dent, Lucas G.</creator><creator>Froldi, Francesca</creator><creator>Forés, Marta</creator><creator>Webster, Kaitlyn</creator><creator>Siegfried, Kellee R.</creator><creator>Kondo, Shu</creator><creator>Harvey, Kieran</creator><creator>Cheng, Louise</creator><creator>Jiménez, Gerardo</creator><creator>Shvartsman, Stanislav Y.</creator><creator>Veraksa, Alexey</creator><general>National Academy of Sciences</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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</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></search><sort><creationdate>20160920</creationdate><title>Minibrain and Wings apart control organ growth and tissue patterning through down-regulation of Capicua</title><author>Yang, Liu ; 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Cic has emerged as a primary sensor of signaling downstream of the receptor tyrosine kinase (RTK)/extracellular signal-regulated kinase (ERK) pathway, but how Cic activity is regulated in different cellular contexts remains poorly understood. We found that the kinase Minibrain (Mnb, ortholog of mammalian DYRK1A), acting through the adaptor protein Wings apart (Wap), physically interacts with and phosphorylates the Cic protein. Mnb and Wap inhibit Cic function by limiting its transcriptional repressor activity. Down-regulation of Cic by Mnb/Wap is necessary for promoting the growth of multiple organs, including the wings, eyes, and the brain, and for proper tissue patterning in the wing. We have thus uncovered a previously unknown mechanism of down-regulation of Cic activity by Mnb and Wap, which operates independently from the ERK-mediated control of Cic. Therefore, Cic functions as an integrator of upstream signals that are essential for tissue patterning and organ growth. Finally, because DYRK1A and CIC exhibit, respectively, prooncogenic vs. tumor suppressor activities in human oligodendroglioma, our results raise the possibility that DYRK1A may also down-regulate CIC in human cells.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>27601662</pmid><doi>10.1073/pnas.1609417113</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adaptor Proteins, Signal Transducing - genetics Animals Biological Sciences Biosensors Body Patterning - genetics Cancer Drosophila - genetics Drosophila - growth & development Drosophila Proteins - biosynthesis Drosophila Proteins - genetics Dyrk Kinases Gene Expression Regulation, Developmental HMGB Proteins - biosynthesis HMGB Proteins - genetics Humans Kinases Neoplasms - genetics Phosphorylation Protein Serine-Threonine Kinases - biosynthesis Protein Serine-Threonine Kinases - genetics Protein-Tyrosine Kinases - genetics Proteins Repressor Proteins - biosynthesis Repressor Proteins - genetics Tissues Wings, Animal - growth & development |
| title | Minibrain and Wings apart control organ growth and tissue patterning through down-regulation of Capicua |
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