RNA-Seq of M1 activated ErbB4-null and WT bone-marrow macrophages.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE168070 | GEO | 2021/04/09
REPOSITORIES: GEO
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Project description:Myocardial ischemia–reperfusion (I/R) injury causes cardiomyocyte death and cardiac dysfunction in part through ferroptosis. Brown adipocytes (BAs) have emerged as endocrine regulators with cardioprotective potential, yet their involvement in ferroptosis modulation during I/R injury remains unclear. Here, we engineered BA sheets and transplanted them onto the ischemic myocardium in a rat I/R model to evaluate therapeutic efficacy. BA sheets transplantation significantly improved cardiac function, reduced infarct size and fibrosis, and mitigated adverse remodeling while enhancing angiogenesis. In vitro, conditioned medium derived from BA sheets promoted cardiomyocyte survival, preserved contractile performance, and inhibited apoptosis and ferroptosis under hypoxia/reoxygenation stress. Mechanistically, these effects were mediated by the activation of the NRG4–ErbB4 axis and its downstream PI3K/AKT and NRF2/HO-1 antioxidant signaling pathways. Our findings demonstrate that engineered BA sheets exert potent cardioprotection against myocardial I/R injury by suppressing ferroptosis in an NRG4–ErbB4–dependent manner, supporting their promise as a therapeutic strategy for ischemic heart disease.
2026-05-29 | GSE309984 | GEO
Project description:RNA-Seq of M1 activated ErbB4-null and WT bone-marrow macrophages.
| PRJNA705981 | ENA
Project description:The four members of the epidermal growth factor receptor (EGFR/ERBB) family form homo- and heterodimers which mediate ligand-specific regulation of many key cellular processes in normal and cancer tissues. While signaling through the EGFR has been extensively studied on the molecular level, signal transduction through ERBB3/ERBB4 heterodimers is less well understood. Here, we generated isogenic mouse Ba/F3 cells that express full-length and functional membrane-integrated ERBB3 and ERBB4 or ERBB4 alone, to serve as a defined cellular model for biological and phosphoproteomics analysis of ERBB3/ERBB4 signaling. ERBB3 co-expression significantly enhanced Ba/F3 cell proliferation upon neuregulin-1 (NRG1) treatment. For comprehensive signaling studies we performed quantitative mass spectrometry (MS) experiments to compare the basal ERBB3/ERBB4 cell phosphoproteome to NRG1 treatment of ERBB3/ERBB4 and ERBB4 cells. We employed a workflow comprising differential isotope labeling with mTRAQ reagents followed by chromatographic peptide separation and final phosphopeptide enrichment prior to MS analysis. Overall, we identified 9686 phosphorylation sites which could be confidently localized to specific residues. Statistical analysis of three replicate experiments revealed 492 phosphorylation sites which were significantly changed in NRG1-treated ERBB3/ERBB4 cells. Bioinformatics data analysis recapitulated regulation of mitogen-activated protein kinase and Akt pathways, but also indicated signaling links to cytoskeletal functions and nuclear biology. Comparative assessment of NRG1-stimulated ERBB4 Ba/F3 cells indicated that ERBB3 did not trigger defined signaling pathways but more broadly enhanced phosphoproteome regulation in cells expressing both receptors. In conclusion, our data provide the first global picture of ERBB3/ERBB4 signaling and provide numerous potential starting points for further mechanistic studies
2016-01-15 | PXD002665 | Pride
Project description:Neuregulin-1 (NRG1) is a paracrine growth factor, secreted by cardiac endothelial cells (Ecs) in conditions of cardiac overload/injury. The current concept is that the cardiac effects of NRG1 are mediated by activation of ERBB4/ERBB2 receptors on cardiomyocytes. However, recent studies have shown that paracrine effects of NRG1 on fibroblasts and macrophages are equally important. Here, we hypothesize that NRG1 autocrine signaling plays a role in cardiac remodeling. We generated EC–specific Erbb4 knockout mice to eliminate endothelial autocrine ERBB4 signaling without affecting paracrine NRG1/ERBB4 signaling in the heart. We first observed no basal cardiac phenotype in these mice up to 32 weeks. We next studied these mice following transverse aortic constriction (TAC), exposure to angiotensin II (Ang II) or myocardial infarction in terms of cardiac performance, myocardial hypertrophy, myocardial fibrosis and capillary density. In general, no major differences between EC–specific Erbb4 knockout mice and control littermates were observed. However, 8 weeks following TAC both myocardial hypertrophy and fibrosis were attenuated by EC–specific Erbb4 deletion, albeit these responses were normalized after 20 weeks. Similarly, 4 weeks after Ang II treatment myocardial fibrosis was less pronounced compared to control littermates. These observations were supported by RNA-sequencing experiments on cultured endothelial cells showing that NRG1 controls the expression of various hypertrophic and fibrotic pathways. Overall, this study shows a role of endothelial autocrine NRG1/ERBB4 signaling in the modulation of hypertrophic and fibrotic responses during early cardiac remodeling. This study contributes to understanding the spatio-temporal heterogeneity of myocardial autocrine and paracrine responses following cardiac injury.
2020-05-15 | GSE150619 | GEO
Project description:ERBB4 is a member of the epidermal growth factor receptor (EGFR)/ERBB subfamily of receptor tyrosine kinases that regulates cellular processes including proliferation, migration and survival. ERBB4 signaling is involved in embryogenesis and homeostasis of adult tissues, but also in human pathologies such as cancer, neurological disorders and cardiovascular diseases. A mass spectrometry screen revealed guanine nucleotide exchange factor (GEF) VAV3, an activator of Rho family GTPases, as a novel ERBB4-interacting protein in breast cancer cells. The ERBB4-VAV3-interaction was confirmed by targeted mass-spectrometry, coimmunoprecipitation experiments, and further defined by demonstrating that kinase activity and tyrosine residues 1022 and 1162 of ERBB4, as well as the intact phosphotyrosine-interacting SH2 domain of VAV3 were necessary for the interaction. ERBB4 was also shown to stimulate tyrosine phosphorylation of the VAV3 activation domain, which is required for GEF activity of VAV proteins. In addition to VAV3, also the other members of the VAV family, VAV1 and VAV2 were shown to coprecipitate with ERBB4. Analyses of the effects of overexpression of dominant-negative VAV3 constructs or downregulation of VAV3 expression by shRNAs in breast cancer cells demonstrated that active VAV3 was involved in ERBB4-stimulated migration. These findings define the VAV GTPases as novel effectors of ERBB4 activity in a signaling pathway relevant for cancer cell migration.
2020-06-24 | PXD019430 | Pride
Project description:Intermittent fasting (IF) improves metabolic health, in part by remodeling white adipose tissue (WAT), yet the underlying mechanisms remain elusive. Here, we show that IF induces coordinated neurovascular remodeling in visceral WAT, marked by increased angiogenesis and sympathetic innervation. Using tissue clearing and three-dimensional visualization, we show that a 16-week IF regimen increases vascular density and sympathetic nerve fiber branching in perigonadal WAT. Transcriptomic profiling reveals robust upregulation of neurotrophic and browning-associated genes, including neuregulin 4 (NRG4), which we identify as a key mediator of sympathetic neurite growth. Co-culture experiments with SH-SY5Y neuron-like cells and WAT explants suggest that IF-treated WAT promotes neurite branching via the NRG4-ErbB4 pathway. Inhibition of NRG4-ErbB4 pathway abrogates this effect, confirming its role in IF-induced sympathetic remodeling. Moreover, analysis of human visceral adipose tissue RNA-seq data shows a strong positive correlation between NRG4 expression and browning gene signatures. Together, these findings uncover a previously unappreciated role of IF in driving sympathetic remodeling of WAT via NRG4, offering mechanistic insights into its metabolic benefits and revealing a potential therapeutic target for obesity-related disorders.
2026-07-13 | E-MTAB-16066 | biostudies-arrayexpress
Project description:Transcriptional profiling of ErbB4-/- mouse liver tissues comparing controls. Two-condition experiment, ErbB4-/- vs. control mouse liver tissues. Biological replicates: 3 controls, 3 ErbB4-/- mice.
2014-09-04 | E-GEOD-61056 | biostudies-arrayexpress
Project description:Like all receptor tyrosine kinases (RTKs), ErbB4 signals through a canonical signaling involving phosphorylation cascades. However, ErbB4 can also signal through a non-canonical mechanism whereby the intracellular domain is released into the cytoplasm by regulated intermembrane proteolysis (RIP) and translocates to the nucleus where it regulates transcription. These different signaling mechanisms depend on the generation of alternative spliced isoforms, a RIP cleavable ErbB4-JMa and an uncleavable ErbB4-JMb. Non-canonical signaling by ErbB4-JMa has been implicated in the regulation of brain, heart, mammary gland, lung, and immune cell development. However, most studies on non-canonical ErbB4 signaling have been performed in vitro due to the lack of an adequate mouse model. We created an ErbB4-JMa specific knock out mouse and demonstrate that RIP-dependent, non-canonical signaling by ErbB4-JMa is required for the regulation of GFAP expression during cortical development. We also show that ErbB4-JMa signaling is not required for the development of the heart, mammary glands, sensory ganglia. Furthermore, we identify genes whose expression during cortical development is regulated by ErbB4, and show that the expression of two of them, CRYM and DBi, depend on ErbB4-JMa. Thus, we provide the first animal model to study the roles of non-canonical RTK in vivo.
2022-08-02 | GSE202063 | GEO
Project description:Hypoxic conditions in high-altitude environments present unique physiological stressors that drive metabolic adaptations, including adipose tissue browning. In this study, we investigated whether hypoxia (11.6% O₂, simulating 5,300 m altitude) could independently induce browning of adipose tissue in mice, apart from cold-induced mechanisms. Hypoxia significantly promoted the formation of multilocular adipocytes in inguinal white adipose tissue (iWAT) and upregulated thermogenic genes (UCP1, PGC-1α, Cox4i1, VEGF), glucose metabolism-related genes (IRS1/2, PDK2, PPARα), and beige adipocyte markers (Car4, UCP1). In contrast, interscapular brown adipose tissue (iBAT) showed minimal response to hypoxia, with no significant change in UCP1 expression. Notably, hypoxia elevated both Nrg4 and phosphorylated ErbB4 in iWAT. In vitro, Nrg4 overexpression in 3T3-L1 adipocytes increased the expression of PKAcα, PGC-1α, and UCP1, while pharmacological inhibition of ErbB4 phosphorylation using Dacomitinib attenuated Nrg4- and hypoxia-induced browning and lipolysis. In vivo, Dacomitinib treatment impaired hypoxia-mediated improvements in WAT browning and glucose tolerance. To explore the structural basis of this interaction, molecular docking and 100-ns molecular dynamics simulations were conducted, revealing strong and stable binding between Nrg4 and ErbB4, with calculated binding energies of −174.26 kcal/mol (MM/GBSA) and −19.5 kcal/mol (PRODIGY). These findings collectively demonstrate that the Nrg4–ErbB4 axis plays a central role in mediating hypoxia-induced browning and metabolic reprogramming of WAT, providing mechanistic insight into adipose tissue plasticity under low-oxygen conditions.
2025-06-11 | GSE298931 | GEO
Project description:Brown Adipocyte Sheets Alleviate Myocardial Ischemia–Reperfusion Injury Through NRG4–ErbB4–Dependent Ferroptosis Inhibition
| PRJNA1364869 | ENA