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

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.

COP9 signalosome subunits protect Capicua from MAPK-dependent and -independent mechanisms of degradation

“…The C-terminal tail of human CSN1 also directly interacts with IκB . We likewise detected a physical interaction between CSN1b and Cic, consistent with a previous mass spectrometry study (Yang et al, 2016), suggesting that direct binding may underlie the effect of CSN1b on Cic stability. Interestingly, Drosophila has a second CSN1 subunit, CSN1a, which lacks the PCI domain and is primarily expressed in the testis (Flybase), and human CSN1 has multiple alternatively spliced isoforms and can be phosphorylated (Fang et al, 2008;Fuzesi-Levi et al, 2014).…”

“…The other highly conserved and essential domains of Cic, the high-mobility group (HMG)-box DNA-binding domain and the C1 motif (Astigarraga et al, 2007), might influence its stability in unstimulated cells. The kinase Minibrain (Mnb) was recently found to phosphorylate Cic on its Nterminus, inhibiting its repressive activity (Yang et al, 2016). Mnb and its adaptor Wings apart do not affect Cic stability, but this finding hints that other mechanisms for Cic regulation may remain to be discovered.…”

A double‐edged sword: The world according to Capicua in cancer

“…a), and the C2 deletion mutant is insensitive for MAPK‐induced downregulation . The ERK‐independent downregulation of CIC by minibrain /DYRK1A is observed in Drosophila wing and eye formation . In addition, bicoid antagonizes downregulation of CIC in anterior patterning of Drosophila .…”

“…(18,33) The ERK-independent downregulation of CIC by minibrain/DYRK1A is observed in Drosophila wing and eye formation. (34) In addition, bicoid antagonizes downregulation of CIC in anterior patterning of Drosophila. (35,36) In this case, bicoid acts as a competitive substrate for MAPK, which renders CIC phosphorylation.…”

Capicua suppresses hepatocellular carcinoma progression by controlling the ETV4–MMP1 axis

“…Cic was first identified in a screen for mutations affecting tissue patterning in Drosophila embryos . In Drosophila , several studies revealed that Cic regulates not only anteroposterior and dorsoventral body patterning but also intestinal stem cell proliferation, wing development, and other processes in development …”