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) 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.
Department of Biology, University of Massachusetts, Boston, MA 02125;
Liu
L
Yang
Department of Biology, University of Massachusetts, Boston, MA 02125;
Sayantanee
S
Paul
Department of Biology, University of Massachusetts, Boston, MA 02125;
Kenneth G
KG
Trieu
Cell Growth and Proliferation Laboratory, Peter MacCallum Cancer Centre, East Melbourne, VIC 3002, Australia;
Lucas G
LG
Dent
Cell Growth and Proliferation Laboratory, Peter MacCallum Cancer Centre, East Melbourne, VIC 3002, Australia;
Francesca
F
Froldi
Instituto de Biología Molecular de Barcelona, Consejo Superior de Investigaciones Científicas, 08028 Barcelona, Spain;
Marta
M
Forés
Department of Biology, University of Massachusetts, Boston, MA 02125;
Kaitlyn
K
Webster
Department of Biology, University of Massachusetts, Boston, MA 02125;
Kellee R
KR
Siegfried
Laboratory of Invertebrate Genetics, National Institute of Genetics, 1111 Yata, Mishima, Shizuoka, Japan;
Shu
S
Kondo
Cell Growth and Proliferation Laboratory, Peter MacCallum Cancer Centre, East Melbourne, VIC 3002, Australia;
Kieran
K
Harvey
Cell Growth and Proliferation Laboratory, Peter MacCallum Cancer Centre, East Melbourne, VIC 3002, Australia;
Louise
L
Cheng
Instituto de Biología Molecular de Barcelona, Consejo Superior de Investigaciones Científicas, 08028 Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats, 08010 Barcelona, Spain;
Gerardo
G
Jiménez
Department of Chemical and Biological Engineering and Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544.
Stanislav Y
SY
Shvartsman
Department of Biology, University of Massachusetts, Boston, MA 02125; alexey.veraksa@umb.edu.
Alexey
A
Veraksa
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000818:Animals; D019521:Body Patterning / Q000235:genetics*; D004330:Drosophila / Q000235:genetics* / Q000254:growth & development; D029721:Drosophila Proteins / Q000096:biosynthesis / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D024002:HMGB Proteins / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D009369:Neoplasms / Q000235:genetics; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics*; D014921:Wings, Animal / Q000254:growth & development; D000097603:Dyrk Kinases
D048868:Adaptor Proteins, Signal Transducing; D029721:Drosophila Proteins; D024002:HMGB Proteins; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D012097:Repressor Proteins; D000097603:Dyrk Kinases; C498610:CIC protein, human; C404284:cic protein, Drosophila; C092066:mnb protein, Drosophila
DYRK1A; capicua; minibrain; organ growth; tissue patterning