Minibrain and Wings apart control organ growth and tissue patterning through down-regulation of Capicua. Author Liu Yang, Sayantanee Paul, Kenneth Trieu, Lucas Dent, Francesca Froldi, Marta Forés, Kaitlyn Webster, Kellee Siegfried, Shu Kondo, Kieran Harvey, Louise Cheng, Gerardo Jiménez, Stanislav Shvartsman, Alexey Veraksa Publication Year 2016 Type Journal Article Abstract 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. Keywords Repressor Proteins, Animals, Drosophila, Drosophila Proteins, Humans, Phosphorylation, Wings, Animal, Gene Expression Regulation, Developmental, Body Patterning, Protein-Tyrosine Kinases, HMGB Proteins, Neoplasms, Adaptor Proteins, Signal Transducing, Protein Serine-Threonine Kinases Journal Proc Natl Acad Sci U S A Volume 113 Issue 38 Pages 10583-8 Date Published 2016 Sep 20 ISSN Number 1091-6490 DOI 10.1073/pnas.1609417113 Alternate Journal Proc Natl Acad Sci U S A PMCID PMC5035877 PMID 27601662 PubMedPubMed CentralGoogle ScholarBibTeXEndNote X3 XML