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

Development. 2017 Jul 15;144(14):2673-2682. doi: 10.1242/dev.148767. Epub 2017 Jun 15.

Abstract

The COP9 signalosome removes Nedd8 modifications from the Cullin subunits of ubiquitin ligase complexes, reducing their activity. Here, we show that mutations in the Drosophila COP9 signalosome subunit 1b (CSN1b) gene increase the activity of ubiquitin ligases that contain Cullin 1. Analysis of CSN1b mutant phenotypes revealed a requirement for the COP9 signalosome to prevent ectopic expression of Epidermal growth factor receptor (EGFR) target genes. It does so by protecting Capicua, a transcriptional repressor of EGFR target genes, from EGFR pathway-dependent ubiquitylation by a Cullin 1/SKP1-related A/Archipelago E3 ligase and subsequent proteasomal degradation. The CSN1b subunit also maintains basal Capicua levels by protecting it from a separate mechanism of degradation that is independent of EGFR signaling. As a suppressor of tumor growth and metastasis, Capicua may be an important target of the COP9 signalosome in cancer.

Keywords: COP9 signalosome; Capicua; Drosophila melanogaster; EGFR; Nedd8; Ubiquitin ligase; Wing disc.

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • COP9 Signalosome Complex
  • Cullin Proteins / genetics
  • Cullin Proteins / metabolism
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / genetics*
  • Drosophila melanogaster / growth & development
  • Drosophila melanogaster / metabolism*
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Eye / growth & development
  • Eye / metabolism
  • Female
  • Genes, Insect
  • HMGB Proteins / genetics
  • HMGB Proteins / metabolism*
  • MAP Kinase Signaling System
  • Male
  • Models, Biological
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism*
  • Mutation
  • Peptide Hydrolases / genetics
  • Peptide Hydrolases / metabolism*
  • Protein Subunits / genetics
  • Protein Subunits / metabolism
  • Proteolysis
  • Receptors, Invertebrate Peptide / genetics
  • Receptors, Invertebrate Peptide / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Ubiquitination
  • Wings, Animal / growth & development
  • Wings, Animal / metabolism

Substances

  • Cullin 1
  • Cullin Proteins
  • Drosophila Proteins
  • HMGB Proteins
  • Multiprotein Complexes
  • Protein Subunits
  • Receptors, Invertebrate Peptide
  • Repressor Proteins
  • cic protein, Drosophila
  • Egfr protein, Drosophila
  • ErbB Receptors
  • Peptide Hydrolases
  • COP9 Signalosome Complex