A genome-wide Drosophila RNAi screen identifies DYRK-family kinases as regulators of NFAT
| العنوان: | A genome-wide Drosophila RNAi screen identifies DYRK-family kinases as regulators of NFAT |
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| المؤلفون: | Sonia Sharma, Sonal Srikanth, Julie Nardone, Stefan Feske, Diana Bolton, Heidi Okamura, Bogdan Tanasa, Anjana Rao, Alina Iuga, Yousang Gwack, Patrick G. Hogan |
| المصدر: | Nature. 441:646-650 |
| بيانات النشر: | Springer Science and Business Media LLC, 2006. |
| سنة النشر: | 2006 |
| مصطلحات موضوعية: | Genetics, Multidisciplinary, NFATC Transcription Factors, Transcription, Genetic, Casein Kinase I, Kinase, Genome, Insect, NFAT, Genomics, Protein Serine-Threonine Kinases, Protein-Tyrosine Kinases, Biology, Hedgehog signaling pathway, Protein Structure, Tertiary, Glycogen Synthase Kinase 3, RNA interference, GSK-3, Animals, Interleukin-2, Drosophila, RNA Interference, Casein kinase 1, Phosphorylation, Transcription factor |
| الوصف: | Down's syndrome is caused by an extra chromosome; somehow a 1.5-fold increase in the dosage of a gene or genes on chromosome 21 causes the wide-reaching effects associated with the condition. A study using ‘knockout’ mice now identifies two genes as candidates for involvement. A 1.5-fold increase in dosage of DSCR1 and DYRK1a destabilizes the regulation of signalling pathways involving the NFAT transcription factor. The discovery follows the surprise finding that NFATc1-4 and calcineurin mutant mice demonstrate nearly all the characteristics of Down's syndrome. In an unrelated paper, a genome-wide RNAi screen reveals conserved regulators of NFAT in Drosophila. NFAT is a purely vertebrate transcription factor, but this work breaks new ground by using Drosophila cells to study the function of a protein artificially introduced from a mammalian species. Pathways regulating the subcellular localization of NFAT proteins are strongly conserved across species and this new approach can identify new regulators of a transcription factor normally expressed in vertebrates. Precise regulation of the NFAT (nuclear factor of activated T cells) family of transcription factors (NFAT1–4) is essential for vertebrate development and function1. 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 nucleus1. NFAT dephosphorylation by calcineurin is countered by distinct NFAT kinases, among them casein kinase 1 (CK1) and glycogen synthase kinase 3 (GSK3)1,2,3,4,5. Here we have used a genome-wide RNA interference (RNAi) screen in Drosophila6,7 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 species8,9, 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. |
| تدمد: | 1476-4687 0028-0836 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::64b8b3f8febaf18932608a61f57359e8Test https://doi.org/10.1038/nature04631Test |
| حقوق: | CLOSED |
| رقم الانضمام: | edsair.doi.dedup.....64b8b3f8febaf18932608a61f57359e8 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14764687 00280836 |
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