Adhesion GPCR ADGRE2 maintains proteostasis to promote progression in acute myeloid leukemia
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1087687 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28341933_1.fastq.gz | Fastqsanger.gz | |||
| SRR28341933_2.fastq.gz | Fastqsanger.gz | |||
| SRR28341934_1.fastq.gz | Fastqsanger.gz | |||
| SRR28341934_2.fastq.gz | Fastqsanger.gz | |||
| SRR28341935_1.fastq.gz | Fastqsanger.gz |
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Project description:Acute myeloid leukemia (AML) is an aggressive and heterogenous hematological malignancy. In elderly patients, AML incidence is high and has a poor prognosis due to a lack of effective therapies. G-protein coupled receptors (GPCRs) play integral roles in physiological processes and human diseases. Particularly, one-third of adhesion GPCRs, the second largest group of GPCRs, are highly expressed in hematopoietic stem and progenitor cells or lineage cells. Therefore, we investigated the role of adhesion GPCRs in AML and whether they could be harnessed as anti-leukemia targets. Systematic screening of the impact of adhesion GPCRs on AML functionality by combined bioinformatic and functional analyses revealed high expression of ADGRE2 in AML, particularly in leukemic stem cells (LSCs), which was associated with poor patient outcomes. Silencing ADGRE2 not only exerted anti-leukemia effects in AML cell lines and AML patient-derived cells in vitro but also delayed AML progression in xenograft models in vivo. Mechanistically, ADGRE2 activated PLC-β/PKC/MEK/ERK signaling to enhance expression of AP-1 and transcriptionally drive expression of DUSP1, a protein phosphatase. DUSP1 de-phosphorylated Ser16 in the J-domain of the co-chaperone DNAJB1, which facilitated DNAJB1-HSP70 interaction and maintenance of proteostasis in AML. Finally, combined inhibition of MEK, AP-1, and DUSP1 exhibited robust therapeutic efficacy in AML xenograft mouse models. Collectively, this study deciphers the roles and mechanisms of ADGRE2 in AML and provides a promising therapeutic strategy for treating AML.
2024-03-19 | GSE261574 | GEO
Project description:The Adhesion GPCR ADGRL2 engages Galpha13 to Enable Epidermal Differentiation
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Project description:The unfolded protein response (UPR) maintains endoplasmic reticulum (ER) proteostasis through the activation of transcription factors such as XBP1s and ATF6. The functional consequences of these transcription factors for ER proteostasis remain poorly defined. Here, we describe methodology that enables orthogonal, small molecule-mediated activation of the UPR-associated transcription factors XBP1s and/or ATF6 in the same cell independent of stress. We employ transcriptomics and quantitative proteomics to evaluate ER proteostasis network remodeling owing to the XBP1s and/or ATF6 transcriptional programs. Furthermore, we demonstrate that the three ER proteostasis environments accessible by activating XBP1s and/or ATF6 differentially influence the folding, trafficking, and degradation of destabilized ER client proteins without globally affecting the endogenous proteome. Our data reveal how the ER proteostasis network is remodeled by the XBP1s and/or ATF6 transcriptional programs at the molecular level and demonstrate the potential for selectively restoring aberrant ER proteostasis of pathologic, destabilized proteins through arm-selective UPR-activation. The unfolded protein response adapts endoplasmic reticulum (ER) proteostasis via stress-responsive transcription factors including XBP1s and ATF6. Here, R. Luke Wiseman and colleagues implement technology for the orthogonal, ligand-dependent activation of XBP1s and/or ATF6 in a single cell. They characterize how XBP1s and/or ATF6 activation impacts ER proteostasis pathway composition and function. Adapted ER environments influence the proteostasis of destabilized protein variants without affecting the endogenous proteome. The work informs the development of proteostasis environment-adapting therapeutics for protein misfolding-related diseases. In order to activate both XBP1s and ATF6 in the same cell, we incorporated DHFR.ATF6 and tet-inducible XBP1s into a HEK293T-REx cell line stably expressing the tet-repressor. The HEK293DYG control cell line expresses tet-inducible eGFP and DHFR.YFP and is used as a control to demonstrate that the addition of doxycycline (dox) and trimethoprim (TMP) do not induce UPR genes. HEK293DYG cells were treated for 12 h with vehicle or 1 μg/mL dox and 10 μM TMP in biological triplicate. Cells were harvested and RNA was extracted using the RNeasy Mini Kit (Qiagen). Genomic DNA was removed by on-column digestion using the RNase-free DNase Set (Qiagen). Data from HEK293DYG cells showed no significant overlap in the ligand-treated transcriptomes obtained from HEK293DAX cells.
2013-04-23 | E-GEOD-44950 | biostudies-arrayexpress
Project description:The unfolded protein response (UPR) maintains endoplasmic reticulum (ER) proteostasis through the activation of transcription factors such as XBP1s and ATF6. The functional consequences of these transcription factors for ER proteostasis remain poorly defined. Here, we describe methodology that enables orthogonal, small molecule-mediated activation of the UPR-associated transcription factors XBP1s and/or ATF6 in the same cell independent of stress. We employ transcriptomics and quantitative proteomics to evaluate ER proteostasis network remodeling owing to the XBP1s and/or ATF6 transcriptional programs. Furthermore, we demonstrate that the three ER proteostasis environments accessible by activating XBP1s and/or ATF6 differentially influence the folding, trafficking, and degradation of destabilized ER client proteins without globally affecting the endogenous proteome. Our data reveal how the ER proteostasis network is remodeled by the XBP1s and/or ATF6 transcriptional programs at the molecular level and demonstrate the potential for selectively restoring aberrant ER proteostasis of pathologic, destabilized proteins through arm-selective UPR-activation. The unfolded protein response adapts endoplasmic reticulum (ER) proteostasis via stress-responsive transcription factors including XBP1s and ATF6. Here, R. Luke Wiseman and colleagues implement technology for the orthogonal, ligand-dependent activation of XBP1s and/or ATF6 in a single cell. They characterize how XBP1s and/or ATF6 activation impacts ER proteostasis pathway composition and function. Adapted ER environments influence the proteostasis of destabilized protein variants without affecting the endogenous proteome. The work informs the development of proteostasis environment-adapting therapeutics for protein misfolding-related diseases. In order to activate both XBP1s and ATF6 in the same cell, we incorporated DHFR.ATF6 and tet-inducible XBP1s into a HEK293T-REx cell line stably expressing the tet-repressor. Selection of a single colony resulted in the HEK293DAX cell line in which XBP1s is induced by doxycycline and DHFR.ATF6 is activated by trimethoprim (TMP; TMP-dependent DHFR.ATF6 activation in HEK293DAX cells will henceforth be referred to as ATF6 activation for simplicity). HEK293DAX cells were treated for 12 h with vehicle, 1 ?g/mL dox, 10 ?M TMP, or both in biological triplicate. Cells were harvested and RNA was extracted using the RNeasy Mini Kit (Qiagen). Genomic DNA was removed by on-column digestion using the RNase-free DNase Set (Qiagen). Data from HEK293DYG cells showed no significant overlap in the ligand-treated transcriptomes obtained from the control HEK293DYG cells.
2013-04-23 | E-GEOD-44949 | biostudies-arrayexpress
Project description:How synapses are assembled and specified in brain is incompletely understood. Latrophilin-3, a postsynaptic adhesion-GPCR, mediates Schaffer-collateral synapse formation in the hippocampus but the mechanisms involved remained unclear. Here we show that Latrophilin-3 organizes synapses by a convergent dual-pathway mechanism by which Latrophilin-3 simultaneously activates GaS/cAMP-signaling and recruits phase-separated postsynaptic protein scaffolds. We found that cell type-specific alternative splicing of Latrophilin-3 controls its G protein coupling mode, resulting in Latrophilin-3 variants that predominantly signal via Gas and cAMP or via Gα12/13. A CRISPR-mediated genetic switch of Latrophilin-3 alternative splicing from a GaS- to a Gα12/13-coupled mode impaired synaptic connectivity similar to the overall deletion of Latrophilin-3, suggesting that GaS/cAMP-signaling by Latrophilin-3 splice variants mediates synapse formation. Moreover, GaS- but not Gα12/13-coupled splice variants of Latrophilin-3 recruit phase-transitioned postsynaptic protein scaffolds that are clustered by binding of presynaptic Latrophilin-3 ligands. Strikingly, neuronal activity promotes alternative splicing of the synaptogenic variant of Latrophilin-3, thereby enhancing synaptic connectivity. Together, these data suggest that activity-dependent alternative splicing of a key synaptic adhesion molecule controls synapse formation by parallel activation of two convergent pathways, GaS/cAMP signaling and the phase separation of postsynaptic protein scaffolds.
2023-10-19 | GSE240791 | GEO