التفاصيل البيبلوغرافية
| العنوان: |
A genome-wide Drosophila RNAi screen identifies DYRK-family kinases as regulators of NFAT. |
| المؤلفون: |
Gwack, Yousang1,2, Sharma, Sonia1,2, Nardone, Julie3, Tanasa, Bogdan1, Iuga, Alina1,2, Srikanth, Sonal1,2, Okamura, Heidi4, Bolton, Diana5, Feske, Stefan1,6, Hogan, Patrick G.1, Rao, Anjana1,2 arao@cbr.med.harvard.edu |
| المصدر: |
Nature. 6/1/2006, Vol. 441 Issue 7093, p646-650. 5p. 2 Diagrams, 1 Chart, 3 Graphs. |
| مصطلحات موضوعية: |
*T cells, *TRANSCRIPTION factors, *CYTOPLASM, *PHOSPHORYLATION, *CALMODULIN, *DROSOPHILA |
| مستخلص: |
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. [ABSTRACT FROM AUTHOR] |
| قاعدة البيانات: |
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