@article {825321,
	title = {A genome-wide Drosophila RNAi screen identifies DYRK-family kinases as regulators of NFAT.},
	journal = {Nature},
	volume = {441},
	year = {2006},
	month = {2006 Jun 1},
	pages = {646-50},
	abstract = {<p>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.</p>},
	keywords = {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},
	issn = {1476-4687},
	doi = {10.1038/nature04631},
	author = {Gwack, Yousang and Sharma, Sonia and Nardone, Julie and Tanasa, Bogdan and Iuga, Alina and Srikanth, Sonal and Okamura, Heidi and Bolton, Diana and Feske, Stefan and Hogan, Patrick G and Rao, Anjana}
}
