Tools and methods for studying the Drosophila JAK/STAT pathway

Chen, Qian; Giedt, Michelle S.; Tang, Lingfeng; Harrison, Douglas A.

doi:10.1016/j.ymeth.2014.03.023

Cited by 27 publications

(22 citation statements)

References 148 publications

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“…ipk2 phenotypes are reminiscent of the small or absent imaginal discs exhibited by some hop and stat92E mutants (36,37). However, modulation of JAK/STAT activity by IPs may be restricted to the imaginal discs, because ipk2 mutants do not seem to have the embryonic segmentation or sex determination defects exhibited by JAK/STAT pathway mutants (38). Given the multitude of products generated by Ipk2 and the growing number of processes regulated by these products and downstream metabolites, such as inositol pyrophosphates, it is not surprising that ipk2 phenotypes cannot be fully rescued by up-regulation of the JAK/STAT pathway.…”

Section: Discussionmentioning

confidence: 99%

Inositol phosphate kinase 2 is required for imaginal disc development in Drosophila

Seeds

Tsui

Sunu

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Inositol phosphate kinase 2 (Ipk2), also known as IP multikinase IPMK, is an evolutionarily conserved protein that initiates production of inositol phosphate intracellular messengers (IPs), which are critical for regulating nuclear and cytoplasmic processes. Here we report that Ipk2 kinase activity is required for the development of the adult fruit fly epidermis. Ipk2 mutants show impaired development of their imaginal discs, the primordial tissues that form the adult epidermis. Although disk tissue seems to specify normally during early embryogenesis, loss of Ipk2 activity results in increased apoptosis and impairment of proliferation during larval and pupal development. The proliferation defect is in part attributed to a reduction in JAK/ STAT signaling, possibly by controlling production or secretion of the pathway's activating ligand, Unpaired. Constitutive activation of the JAK/STAT pathway downstream of Unpaired partially rescues the disk growth defects in Ipk2 mutants. Thus, IP production is essential for proliferation of the imaginal discs, in part, by regulating JAK/STAT signaling. Our work demonstrates an essential role for Ipk2 in producing inositide messengers required for imaginal disk tissue maturation and subsequent formation of adult body structures and provides molecular insights to signaling pathways involved in tissue growth and stability during development.inositol phosphates | inositol phosphate multikinase | Ipk2 | IPMK | Upd A t the confluence of numerous signaling pathways is phospholipase C (PLC)-mediated production of the second messenger inositol 1,4,5-trisphosphate (IP 3 ), a key regulator of intracellular calcium release (1). IP 3 also serves as an essential substrate for the synthesis of inositol phosphates (IPs) and pyrophosphates (PP-IPs) that are critical for eukaryotic cellular function in their own right (2-6). Phosphorylation of IP 3 by conserved inositol phosphate kinases (IPKs) leads to the synthesis of complex pools of different IP species (6). Insights into the cellular functions of IPs have been gleaned by perturbing their synthesis through genetic manipulations of the IPKs. Consequently, defects in specific cellular processes were attributed to losses of particular IPs. This revealed that IPs are specific regulators of diverse cellular processes, such as transcription, chromatin remodeling, DNA repair, RNA editing, and RNA export (3-7).An essential enzyme for the conversion of IP 3 to the array of IP and PP-IP species found in cells is the evolutionarily conserved inositol phosphate kinase 2 (Ipk2, Fig. 1A), which is also known as IP multikinase (IPMK) (4). Ipk2 was first identified in yeast as a nuclear enriched protein whose activities toward the 6-and 3-positions on the inositol ring sequentially convert IP 3 to IP 4 , and then IP 5 (Fig. 1A) (8-10). Yeast Ipk2 mutants that fail to produce IP 4 and IP 5 exhibit defects in transcriptional responses and chromatin remodeling (3). Additional "multikinase" activities described for certain Ipk2 orthologs indicate an array ...

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Section: Discussionmentioning

confidence: 99%

Inositol phosphate kinase 2 is required for imaginal disc development in Drosophila

Seeds

Tsui

Sunu

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Pathway enrichment analysis: Pathway enrichment analysis was performed using two different methods. The first was “Pathway-tools” (Chen et al, 2014), the stand-alone version of the tool integrated into the Biocyc online resource (Caspi et al, 2014). This tool allows additional visualization of the data on a metabolic pathway map (both metabolomic and transcriptomic), but this tool does not allow the definition of a background metabolic set (all metabolites measured by the used platform).…”

Section: Methodsmentioning

confidence: 99%

Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity

et al. 2016

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SUMMARY Induction of trained immunity (innate immune memory) is mediated by activation of immune and metabolic pathways that result in epigenetic rewiring of cellular functional programs. Through network-level integration of transcriptomics and metabolomics data, we identify glycolysis, glutaminolysis, and the cholesterol synthesis pathway as indispensable for the induction of trained immunity by β-glucan in monocytes. Accumulation of fumarate, due to glutamine replenishment of the TCA cycle, integrates immune and metabolic circuits to induce monocyte epigenetic reprogramming by inhibiting KDM5 histone demethylases. Furthermore, fumarate itself induced an epigenetic program similar to β-glucan-induced trained immunity. In line with this, inhibition of glutaminolysis and cholesterol synthesis in mice reduced the induction of trained immunity by β-glucan. Identification of the metabolic pathways leading to induction of trained immunity contributes to our understanding of innate immune memory and opens new therapeutic avenues.

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“…The JAK/STAT signaling pathway exerts many conserved functions from insects to mammals, which include inflammation, cell proliferation, cell migration and stem cell maintenance (Hou et al, 2002;Arbouzova and Zeidler, 2006;Hombria and Sotillos, 2013;Chen et al, 2014). In Drosophila, the cytokine-like Upd ligands bind to the transmembrane receptor Dome and this event recruits Hop, the Drosophila JAK, which phosphorylates and activates Stat92E, the sole STAT transcription factor in Drosophila.…”

Section: Introductionmentioning

confidence: 99%

Spatiotemporal regulation of cell fusion by JNK and JAK/STAT signaling during Drosophila wound healing

Lee

Park

et al. 2017

Journal of Cell Science

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Cell-cell fusion is widely observed during development and disease, and imposes a dramatic change on participating cells. Cell fusion should be tightly controlled, but the underlying mechanism is poorly understood. Here, we found that the JAK/STAT pathway suppressed cell fusion during wound healing in the Drosophila larval epidermis, restricting cell fusion to the vicinity of the wound. In the absence of JAK/STAT signaling, a large syncytium containing a 3-fold higher number of nuclei than observed in wild-type tissue formed in wounded epidermis. The JAK/STAT ligand-encoding genes upd2 and upd3 were transcriptionally induced by wounding, and were required for suppressing excess cell fusion. JNK (also known as Basket in flies) was activated in the wound vicinity and activity peaked at ∼8 h after injury, whereas JAK/STAT signaling was activated in an adjoining concentric ring and activity peaked at a later stage. Cell fusion occurred primarily in the wound vicinity, where JAK/STAT activation was suppressed by fusion-inducing JNK signaling. JAK/ STAT signaling was both necessary and sufficient for the induction of βPS integrin (also known as Myospheroid) expression, suggesting that the suppression of cell fusion was mediated at least in part by integrin protein.

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Tools and methods for studying the Drosophila JAK/STAT pathway

Cited by 27 publications

References 148 publications

Inositol phosphate kinase 2 is required for imaginal disc development in Drosophila

Inositol phosphate kinase 2 is required for imaginal disc development in Drosophila

Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity

Spatiotemporal regulation of cell fusion by JNK and JAK/STAT signaling during Drosophila wound healing

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