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ATP-Competitive Partial Antagonists—'PAIR's—Segregate IRE1α’s RNase-Mediated Biological Outputs

ABSTRACT: ATP-Competitive Partial Antagonists—'PAIR's—Segregate IRE1α’s RNase-Mediated Biological Outputs

PROVIDER: PRJNA690946 | ENA |

REPOSITORIES: ENA

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ATP-Competitive Partial Antagonists—'PAIR's—Segregate IRE1α’s RNase-Mediated Biological Outputs

Project description:During mammalian cell growth and differentiation, the unfolded protein response (UPR) homeostatically adjusts endoplasmic reticulum (ER) protein-folding capacity to match changing cellular secretory demands. However, under high/chronic ER stress conditions the UPR triggers apoptosis. This dichotomy is promoted in part by differential activation levels of the ER transmembrane kinase/endoribonuclease (RNase) IRE1a. IRE1a kinase auto-phosphorylation operates as a rheostat to control downstream RNase-induced outputs that either sustain adaptive ER protein-folding or cause apoptosis. We have previously shown that IRE1a’s RNase activity can be activated or fully inactivated by ATP-competitive kinase inhibitors. Here we developed a new class of ATP-competitive kinase inhibitors that partially antagonize the RNase of IRE1a at full occupancy. An atomic level resolution co-crystal structure shows that these small molecule partial antagonists—which we named ‘PAIR’s for (Partial Antagonists of IRE1a RNase)—occupy the ATP-binding site of IRE1a and partially displace a helix (helix aC) in the kinase domain that forms part of a dimeric interface. In insulin-producing beta cells, PAIRs permit adaptive XBP1 mRNA splicing, while quelling destructive/terminal outputs from extra-XBP1 mRNA endonucleolytic decay, thus preventing apoptosis. Preservation of XBP1 splicing by PAIRs permits B lymphocytes to differentiate into immunoglobulin-producing plasma cells. In summary, we propose that an intermediate RNase-inhibitory “sweet spot,” achieved by PAIR-bound IRE1a, may capture a structural conformation naturally available to IRE1a that could represent a desirable therapeutic state for drugging this master UPR sensor/effector.

2021-06-01 | GSE164496 | GEO

Transcriptional profiling of ATP-competitive mTOR inhibitors reveals mTORC1 and mTORC2 specific regulatory networks

Project description:The mammalian target of rapamycin (mTOR) is a central regulator of cell growth and proliferation in response to growth factor and nutrient signaling. Consequently, this kinase is implicated in metabolic diseases including cancer and diabetes so there is great interest in understanding mTOR regulatory networks. mTOR exists in two functionally distinct complexes, mTORC1 and mTORC2, and whereas the natural product rapamycin only inhibits a subset of mTORC1 functions, recently developed ATP-competitive mTOR inhibitors have revealed new roles for both complexes. To examine the complete spectrum of mTOR responsive cellular processes, we compared the transcriptional profiles of mammalian cells treated with rapamycin versus the ATP-competitive inhibitor PP242. Our analysis provides a genome-wide view of the transcriptional outputs of mTOR signaling that are insensitive to rapamycin. Gene expression in mouse NIH3T3 cells was measured after 18 hour treatment with DMSO (control), 50 nM rapamycin, or 2 uM PP242. Four independent experiments were performed for each condition.

2011-03-15 | E-GEOD-27784 | biostudies-arrayexpress

Transcriptional profiling of ATP-competitive mTOR inhibitors reveals mTORC1 and mTORC2 specific regulatory networks

2011-03-15 | GSE27784 | GEO

GCN2 kinase Activation by ATP-competitive Kinase Inhibitors

Project description:GCN2 kinase Activation by ATP-competitive Kinase Inhibitors

| PRJNA780901 | ENA

RNA-seq of prostate cancer cell lines with acquired resistance to AKT inhibitors GDC-0068 (ATP competitive) or MK206 (allosteric)

Project description:Goal: Study resistance mechanisms to ATP-competitive vs. allosteric AKT inhibitors, in prostate cancer Methods: RNA-sequencing Results: Resistance to the ATP-competitive inhibitor GDC-0068 was driven by compensatory activity of parallel signaling pathways

2020-01-24 | GSE139178 | GEO

Activation of the IRE1 RNase through remodeling of the kinase front pocket by ATP-competitive ligands.

Project description: Not available

| S-EPMC7736581 | biostudies-literature

The Oscillating miRNA 959-964 cluster impacts Drosophila feeding time and other circadian outputs.

Project description:This SuperSeries is composed of the following subset Series: GSE40894: The Oscillating miRNA 959-964 cluster impacts Drosophila feeding time and other circadian outputs [expression]. GSE40943: The Oscillating miRNA 959-964 cluster impacts Drosophila feeding time and other circadian outputs [miRNA-seq]. Refer to individual Series

2012-11-02 | E-GEOD-40981 | biostudies-arrayexpress

GCN2 kinase Activation by ATP-competitive Kinase Inhibitors

Project description:Purpose: Use next generation sequencing to determine which CRISPR knockouts confer resistance to EGFR inhibitors and to determine which cellular pathways get upregulated in response to neratinib.

2021-12-31 | GSE188958 | GEO

CCL171, T47D, MDA-MB231 cell lines: stimulation with BMP7 and antagonists

Project description:Methods: We used an ex vivo culture model and measured gene expression changes in human lung fibroblasts after stimulation with BMPs and their antagonists using HEEBO microarrays. The in vitro data were correlated with in vivo observations in published expression datasets of human lung adenocarcinomas. Results: We have systematically analyzed the response to BMP2, BMP4, BMP7 and their antagonists, gremlin and noggin, to define common and specific gene expression patterns. A BMP2 induced gene expression signature was defined, which is specific for stromal fibroblasts. Gene expression profiles from lung adenocarcinoma biopsies were analyzed to determine the prognostic significance of the Fibroblast specific BMP2 induced gene list. This gene list successfully segregated patients with different prognostic outcome in 3 datasets. In a small dataset (Garber et al.) there was a strong trend for a worse prognosis of patients with adenocarcinomas of all stages over-expressing the Fibroblast specific BMP2 induced gene list. In two larger datasets with stage I adenocarcinomas we observed a significantly worse disease-free (p=0.002, Lee et al. and p=0.002, Bhattacharjee et al.) and overall survival (p=0.0002). Conclusions: The effects of BMPs and their antagonists are heterogeneous in different cell types. The gene expression pattern induced by BMP2 in primary lung fibroblasts may predict outcomes of patients with lung adenocarcinomas. A stimulus or stress experiment design type is where that tests response of an organism(s) to stress/stimulus. e.g. osmotic stress, behavioral treatment stimulus_or_stress_design

2016-02-19 | E-GEOD-66108 | biostudies-arrayexpress

Competitive RNA Pair Controls Gastric Cancer Metastasis

Project description:Competitive RNA Pair Controls Gastric Cancer Metastasis

| PRJNA418152 | ENA