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A genome-wide Drosophila RNAi screen identifies DYRK-family kinases as regulators of NFAT.

Precise regulation of the NFAT (nuclear factor of activated T cells) family of transcription factors (NFAT1-4) is essential for vertebrate development and function. In resting cells, NFAT proteins are heavily phosphorylated and reside in the cytoplasm; in cells exposed to stimuli that raise intracellular free Ca2+ levels, they are dephosphorylated by the calmodulin-dependent phosphatase calcineurin and translocate to the nucleus. NFAT dephosphorylation by calcineurin is countered by distinct NFAT kinases, among them casein kinase 1 (CK1) and glycogen synthase kinase 3 (GSK3). Here we have used a genome-wide RNA interference (RNAi) screen in Drosophila to identify additional regulators of the signalling pathway leading from Ca2+-calcineurin to NFAT. This screen was successful because the pathways regulating NFAT subcellular localization (Ca2+ influx, Ca2+-calmodulin-calcineurin signalling and NFAT kinases) are conserved across species, even though Ca2+-regulated NFAT proteins are not themselves represented in invertebrates. Using the screen, we have identified DYRKs (dual-specificity tyrosine-phosphorylation regulated kinases) as novel regulators of NFAT. DYRK1A and DYRK2 counter calcineurin-mediated dephosphorylation of NFAT1 by directly phosphorylating the conserved serine-proline repeat 3 (SP-3) motif of the NFAT regulatory domain, thus priming further phosphorylation of the SP-2 and serine-rich region 1 (SRR-1) motifs by GSK3 and CK1, respectively. Thus, genetic screening in Drosophila can be successfully applied to cross evolutionary boundaries and identify new regulators of a transcription factor that is expressed only in vertebrates.

Pubmed ID: 16511445


  • Gwack Y
  • Sharma S
  • Nardone J
  • Tanasa B
  • Iuga A
  • Srikanth S
  • Okamura H
  • Bolton D
  • Feske S
  • Hogan PG
  • Rao A



Publication Data

June 1, 2006

Associated Grants


Mesh Terms

  • Animals
  • Casein Kinase I
  • Drosophila
  • Genome, Insect
  • Genomics
  • Glycogen Synthase Kinase 3
  • Interleukin-2
  • NFATC Transcription Factors
  • Phosphorylation
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases
  • Protein-Tyrosine Kinases
  • RNA Interference
  • Transcription, Genetic