Minibrain and Wings apart control organ growth and tissue patterning through down-regulation of Capicua.

TitleMinibrain and Wings apart control organ growth and tissue patterning through down-regulation of Capicua.
Publication TypeJournal Article
Year of Publication2016
AuthorsYang, L, Paul, S, Trieu, KG, Dent, LG, Froldi, F, Forés, M, Webster, K, Siegfried, KR, Kondo, S, Harvey, K, Cheng, L, Jiménez, G, Shvartsman, SY, Veraksa, A
JournalProc Natl Acad Sci U S A
Date Published2016 Sep 20
KeywordsAdaptor Proteins, Signal Transducing, Animals, Body Patterning, Drosophila, Drosophila Proteins, Gene Expression Regulation, Developmental, HMGB Proteins, Humans, Neoplasms, Phosphorylation, Protein Serine-Threonine Kinases, Protein-Tyrosine Kinases, Repressor Proteins, Wings, Animal

<p>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.</p>

Alternate JournalProc Natl Acad Sci U S A
PubMed ID27601662
PubMed Central IDPMC5035877
Grant ListR01 GM086537 / GM / NIGMS NIH HHS / United States
R01 GM105813 / GM / NIGMS NIH HHS / United States
R01 HD085870 / HD / NICHD NIH HHS / United States