Transcriptional targets of EphB2 and Ephrin-A4 signaling in epidermal keratinocytes
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE26523 | GEO | 2011/03/01
SECONDARY ACCESSION(S): PRJNA136717
REPOSITORIES: GEO
Similar Datasets
Project description:Human epidermal keratinocytes were treated with 25 ng.ml EphB2 or EFNA4, both as-Fc conjugates (Sigma). Human epidermal keratinocytes are treated with 25 ng/ml EphB2 or EFNA4 Fc conjugates in a 48hr time course.
2011-03-01 | E-GEOD-26523 | biostudies-arrayexpress
Project description:Both ephrins and their receptors are membrane bound, restricting their interactions to the sites of direct cell-to-cell interfaces. They are widely expressed, often co-expressed and regulate developmental processes, cell adhesion, motility, survival, proliferation, and differentiation. Both tumor suppressor and oncogene activities are ascribed to EFNs and Ephs in various contexts. A major conundrum regarding the EFN/Eph system concerns their large number and functional redundancy, given the promiscuous cross-activation of ligands and receptors and the overlapping intracellular signaling pathways. To address this issue, we treated human epidermal keratinocytes with 5 EFNAs individually and defined the transcriptional responses in the cells. We found that a large set of genes is coregulated by all EFNAs. However, while the responses to EFNA3, EFNA 4 and EFNA 5 are identical, the responses to EFNA1 and EFNA2 are characteristic and distinctive. All EFNAs induce epidermal differentiation markers and suppress cell adhesion genes, especially integrins. Ontological analysis shows that all EFNAs induce cornification and keratin genes, while suppressing wound-healing associated, signaling, receptor and ECM associated genes. Transcriptional targets of AP1 are selectively suppressed by EFNAs. EFNA1 and EFNA2, but not the EFNA3, EFNA4, EFNA5 cluster, regulate the members of the ubiquitin-associated proteolysis genes. EFNA1 specifically induces collagen production. Our results demonstrate that the EFN-Eph interactions in the epidermis, while promiscuous, are not redundant but specific. This suggests that different members of the EFN/Eph system have specific, clearly demarcated functions. Human epidermal keratinocytes are treated with 25 ng/ml EFNA1; EFNA2; EFNA3; EFNA4 or EFNA5 (all as Fc conjugates) for 24h.
2011-01-10 | E-GEOD-26521 | biostudies-arrayexpress
Project description:HIV Associated Neurocognitive Disorder (HAND) is a condition behaviorally characterized by cognitive and neurological impairments, and pathologically characterized by neuroinflammation and a loss of synaptic integrity and function. Although therapeutics exist to increase the lifespan of people living with HIV, they are not effective at preventing HIV induced neuronal damage and the prevalence of HAND remains virtually unchanged. We observed an increase in expression of ephrin-B/EphB in post-mortem CNS specimen of people who lived with HIV and brain pathology. Given the previously recognized impact of EphB2 on inflammation in the periphery, the functional role of EphB2-mediated ephrin-B reverse signaling on microglia was assessed. A a pro-inflammatory and antiviral mRNA expression profile was observed. The stimulation produced condirioned media, including secreted inflammatory factors, that were sufficient to induce non-cell contact-dependent neurotoxicity. Finally, knockdown of microglial ephrin-B1, EphB2 binding partner, resulted in a partial alleviation of the microglial pro-inflammatory signature and subsequent neurotoxicity. In this study, we show that elevated EphB2, and its reverse signaling through ephrin-B1 in microglia, can drive neuroinflammation and toxicity suggesting this pathway can mediate neurotoxicity in neuroHIV. Furthermore, we propose that this neuroinflammatory mechanism may play a role in promoting other neurodegenerative diseases.
2024-06-01 | GSE260757 | GEO
Project description:The role of Eph/ephrin signaling in numerous biological processes has been established. However, Eph/ephrin signaling has been shown to have complex role in tumor progression. The role of EphB2 receptor in the progression of cutaneous squamous cell carcinoma (cSCC) has not been studied before. EphB2 is significantly overexpressed in cSCC cells compared with normal human epidermal keratinocytes (NHEKs). We used microarray based global gene expression profiling to study the effect of EphB2 knockdown on the expression of different genes in cSCC cells. cSCC cell lines (n=3) were transfected with either control or EphB2 siRNA (75 nM) and incubated for 72 hours. Total RNA was extracted and processed expression profiling with GeneChip 3’ IVT Express Kit according to manufacturer’s protocol.
2015-08-27 | E-GEOD-66361 | biostudies-arrayexpress
Project description:The role of Eph/ephrin signaling in numerous biological processes has been established. However, Eph/ephrin signaling has been shown to have complex role in tumor progression. The role of EphB2 receptor in the progression of cutaneous squamous cell carcinoma (cSCC) has not been studied before. EphB2 is significantly overexpressed in cSCC cells compared with normal human epidermal keratinocytes (NHEKs). We used microarray based global gene expression profiling to study the effect of EphB2 knockdown on the expression of different genes in cSCC cells.
2015-08-27 | GSE66361 | GEO
Project description:Both ephrins and their receptors are membrane bound, restricting their interactions to the sites of direct cell-to-cell interfaces. They are widely expressed, often co-expressed and regulate developmental processes, cell adhesion, motility, survival, proliferation, and differentiation. Both tumor suppressor and oncogene activities are ascribed to EFNs and Ephs in various contexts. A major conundrum regarding the EFN/Eph system concerns their large number and functional redundancy, given the promiscuous cross-activation of ligands and receptors and the overlapping intracellular signaling pathways. To address this issue, we treated human epidermal keratinocytes with 5 EFNAs individually and defined the transcriptional responses in the cells. We found that a large set of genes is coregulated by all EFNAs. However, while the responses to EFNA3, EFNA 4 and EFNA 5 are identical, the responses to EFNA1 and EFNA2 are characteristic and distinctive. All EFNAs induce epidermal differentiation markers and suppress cell adhesion genes, especially integrins. Ontological analysis shows that all EFNAs induce cornification and keratin genes, while suppressing wound-healing associated, signaling, receptor and ECM associated genes. Transcriptional targets of AP1 are selectively suppressed by EFNAs. EFNA1 and EFNA2, but not the EFNA3, EFNA4, EFNA5 cluster, regulate the members of the ubiquitin-associated proteolysis genes. EFNA1 specifically induces collagen production. Our results demonstrate that the EFN-Eph interactions in the epidermis, while promiscuous, are not redundant but specific. This suggests that different members of the EFN/Eph system have specific, clearly demarcated functions.
2011-01-10 | GSE26521 | GEO
Project description:Objectives: Eph/Ephrin cell-cell signaling is emerging as a key player in tissue fibrogenesis. The aim of this study was to test the hypothesis that the receptor tyrosine kinase EphB2 mediates dermal fibrosis in systemic sclerosis (SSc). Methods: We assessed normal and SSc human skin biopsies for EphB2 expression. The in vivo role of EphB2 in skin fibrosis was investigated by subjecting EphB2-knockout mice to both bleomycin-induced and tight skin (Tsk1/+) genetic mouse models. EphB2 kinase-dead and overactive point mutant mice were used to evaluate the role of EphB2 forward signaling in bleomycin-induced dermal fibrosis. In vitro studies were performed on dermal fibroblasts from SSc patients and healthy controls, which was followed by in vivo analysis of fibroblast-specific EphB2 deficient mice. Results: Expression of EphB2 is upregulated in SSc skin tissue and explanted SSc dermal fibroblasts compared to healthy controls. EphB2 expression is elevated in two animal models of dermal fibrosis. In mice, EphB2 drives dermal fibrosis in both the bleomycin and the Tsk1/+ models of skin fibrosis. EphB2 forward signaling is a critical mediator of dermal fibrosis. Transforming growth factor-β (TGFβ) cytokines upregulate EphB2 in dermal fibroblasts via non-canonical TGFβ/SMAD signaling and silencing EphB2 in dermal fibroblasts is sufficient to dampen TGFβ-induced fibroblast-to-myofibroblast differentiation. Moreover, mice with fibroblast-specific deletion of EphB2 showed impaired fibroblast-to-myofibroblast differentiation and reduced skin fibrosis upon bleomycin challenge. Conclusion: Our data implicate EphB2 overexpression and kinase-mediated forward signaling in the development of dermal fibrosis in SSc. EphB2 thus represents a potential new therapeutic target for SSc.
2024-04-10 | GSE253089 | GEO
Project description:Both ephrins (EFNs) and their receptors (Ephs) are membrane-bound, restricting their interactions to the sites of direct cell-to-cell interfaces. They are widely expressed, often co-expressed, and regulate developmental processes, cell adhesion, motility, survival, proliferation, and differentiation. Both tumor suppressor and oncogene activities are ascribed to EFNs and Ephs in various contexts. A major conundrum regarding the EFN/Eph system concerns their large number and functional redundancy given the promiscuous cross-activation of ligands and receptors and the overlapping intracellular signaling pathways. To address this issue, we treated human epidermal keratinocytes with five EFNAs individually and defined the transcriptional responses in the cells. We found that a large set of genes is coregulated by all EFNAs. However, although the responses to EFNA3, EFNA4, and EFNA5 are identical, the responses to EFNA1 and EFNA2 are characteristic and distinctive. All EFNAs induce epidermal differentiation markers and suppress cell adhesion genes, especially integrins. Ontological analysis showed that all EFNAs induce cornification and keratin genes while suppressing wound healing-associated, signaling, receptor, and extracellular matrix-associated genes. Transcriptional targets of AP1 are selectively suppressed by EFNAs. EFNA1 and EFNA2, but not the EFNA3, EFNA4, EFNA5 cluster, regulate the members of the ubiquitin-associated proteolysis genes. EFNA1 specifically induces collagen production. Our results demonstrate that the EFN-Eph interactions in the epidermis, although promiscuous, are not redundant but specific. This suggests that different members of the EFN/Eph system have specific, clearly demarcated functions.
| S-EPMC3059010 | biostudies-literature
Project description:Local cerebral hypoperfusion causes ischemic stroke while driving multiple cell-specific responses including inflammation, glutamate-NMDAR-mediated neurotoxicity, edema formation and angiogenesis. Despite the relevance of these pathophysiological mechanisms for disease progression and outcome, molecular determinants controlling the onset of these processes are only partially understood. In this context, our study intended to investigate the functional role of EphB2 – a receptor tyrosine kinase that is crucial for synapse function and binds to membrane-associated ephrin-B ligands. Cerebral ischemia was induced in EphB2-deficient mice by transient middle cerebral artery occlusion followed by different times (6, 12, 24 and 48 h) of reperfusion. Histological, neurofunctional and transcriptome analyses indicated an increase in EphB2 phosphorylation under these conditions and attenuated progression of stroke in EphB2-deficient mice. Moreover, while infiltration of microglia/macrophages and astrocytes into the peri-infarct region was not altered, expression of the pro-inflammatory mediators MCP-1 or IL-6 was decreased in these mice. In fact, in vitro analyses indicated that binding of EphB2 to astrocytic ephrin-B ligands stimulates NF-κB-mediated cytokine expression via the MAPK pathway. Further magnetic resonance imaging of the EphB2-deficient ischemic brain revealed a lower level of neuronal cytotoxic edema formation within 6 h upon onset of reperfusion. On the mechanistic level, absence of neuronal EphB2 decreased the mitochondrial Ca2+ load upon activation of NMDAR but not AMPAR. Moreover, activation of EphB2 by ephrin-B2 enhanced the NMDA-evoked excitotoxic neuronal cell death in vitro while neuron-specific loss of ephrin-B2 reduced the extent of cerebral tissue damage in the acute phase of ischemic stroke. Collectively, EphB2 may promote the immediate response to an ischemia-reperfusion event in the central nervous system by (i) pro-inflammatory activation of astrocytes via ephrin-B-dependent signalling and (ii) amplification of the NMDA-evoked neuronal excitotoxicity.
2019-02-13 | GSE120565 | GEO
Project description:Current therapeutic strategies for treating non-alcoholic steatohepatitis (NASH) have failed to alleviate liver fibrosis, which is a devastating feature leading to hepatic dysfunction. Here, we integrated single-nucleus transcriptomics and epigenomics to characterize all major liver cell types during NASH development in mice and humans. The bifurcation of hepatocyte trajectory with NASH progression was conserved between mouse and human. At the non-alcoholic fatty liver (NAFL) stage, hepatocytes exhibited metabolic adaptation, whereas at the NASH stage, a subset of hepatocytes was enriched for the signatures of cell adhesion and migration, which was mainly demarcated by receptor tyrosine kinase EphB2. EphB2, acting as a downstream effector of Notch signaling in hepatocytes, was sufficient to induce cell-autonomously inflammation. Knockdown of Ephb2 in hepatocytes ameliorated inflammation and fibrosis in NASH. Thus, EphB2 expressing hepatocytes contribute to NASH progression and may serve as a potential therapeutic target.
2023-02-08 | GSE189600 | GEO