Genome-wide RNAi analysis of JAK/STAT signaling components in Drosophila.
The cytokine-activated Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway plays an important role in the control of a wide variety of biological processes. When misregulated, JAK/STAT signaling is associated with various human diseases, such as immune disorders and tumorigenesis. To gain insights into the mechanisms by which JAK/STAT signaling participates in these diverse biological responses, we carried out a genome-wide RNA interference (RNAi) screen in cultured Drosophila cells. We identified 121 genes whose double-stranded RNA (dsRNA)-mediated knockdowns affected STAT92E activity. Of the 29 positive regulators, 13 are required for the tyrosine phosphorylation of STAT92E. Furthermore, we found that the Drosophila homologs of RanBP3 and RanBP10 are negative regulators of JAK/STAT signaling through their control of nucleocytoplasmic transport of STAT92E. In addition, we identified a key negative regulator of Drosophila JAK/STAT signaling, protein tyrosine phosphatase PTP61F, and showed that it is a transcriptional target of JAK/STAT signaling, thus revealing a novel negative feedback loop. Our study has uncovered many uncharacterized genes required for different steps of the JAK/STAT signaling pathway.
Baeg
Gyeong-Hun
GH
Department of Genetics, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA.
Zhou
Rui
R
Perrimon
Norbert
N
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000201:enzymology / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology; D029721:Drosophila Proteins / Q000235:genetics / Q000502:physiology*; D053613:Janus Kinase 1; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000502:physiology; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology; D050791:STAT Transcription Factors; D015398:Signal Transduction / Q000235:genetics* / Q000502:physiology; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism
D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D012097:Repressor Proteins; D050791:STAT Transcription Factors; C460659:Socs36E protein, Drosophila; C105675:Stat92E protein, Drosophila; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; D053613:Janus Kinase 1; D017027:Protein Tyrosine Phosphatases; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C107962:Ptp61F protein, Drosophila