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Proc Natl Acad Sci U S A. 2016 Sep 20;113(38):10583-8. doi: 10.1073/pnas.1609417113. Epub 2016 Sep 6.

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

Author information

1
Department of Biology, University of Massachusetts, Boston, MA 02125;
2
Cell Growth and Proliferation Laboratory, Peter MacCallum Cancer Centre, East Melbourne, VIC 3002, Australia;
3
Instituto de Biología Molecular de Barcelona, Consejo Superior de Investigaciones Científicas, 08028 Barcelona, Spain;
4
Laboratory of Invertebrate Genetics, National Institute of Genetics, 1111 Yata, Mishima, Shizuoka, Japan;
5
Instituto de Biología Molecular de Barcelona, Consejo Superior de Investigaciones Científicas, 08028 Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats, 08010 Barcelona, Spain;
6
Department of Chemical and Biological Engineering and Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544.
7
Department of Biology, University of Massachusetts, Boston, MA 02125; alexey.veraksa@umb.edu.

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:

DYRK1A; capicua; minibrain; organ growth; tissue patterning

PMID:
27601662
PMCID:
PMC5035877
DOI:
10.1073/pnas.1609417113
[Indexed for MEDLINE]
Free PMC Article

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