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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Animals
  • Body Patterning / genetics*
  • Drosophila / genetics*
  • Drosophila / growth & development
  • Drosophila Proteins / biosynthesis
  • Drosophila Proteins / genetics*
  • Gene Expression Regulation, Developmental
  • HMGB Proteins / biosynthesis
  • HMGB Proteins / genetics*
  • Humans
  • Neoplasms / genetics
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / biosynthesis
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Tyrosine Kinases / genetics*
  • Repressor Proteins / biosynthesis
  • Repressor Proteins / genetics*
  • Wings, Animal / growth & development

Substances

  • Adaptor Proteins, Signal Transducing
  • CIC protein, human
  • Drosophila Proteins
  • HMGB Proteins
  • Repressor Proteins
  • cic protein, Drosophila
  • Dyrk kinase
  • mnb protein, Drosophila
  • Protein-Tyrosine Kinases
  • Protein-Serine-Threonine Kinases