Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA134487 | ENA |
REPOSITORIES: ENA
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Project description:MEK5 is activated by shear stress in large vessel endothelial cells (ECs) and contributes to the suppression of pro-inflammatory changes in the arterial wall. We used microarray analyses of total RNA from MEK5/CA-transduced HDMECs compared to LacZ control-transduced HDMECs to identify distinct classes of several regulated genes, including KLF4, eNOS, and ICAM. We conclude that MEK5 activation by shear stress may modulate inflammatory responses in the microvasculature, and these actions are partly mediated by KLF4. Total RNA was isolated from 8 separate paired (derived from same primary isolate) MEK5/CA and LacZ transduced HDMEC lines
2010-12-31 | E-GEOD-25145 | biostudies-arrayexpress
Project description:MEK5 is activated by shear stress in large vessel endothelial cells (ECs) and contributes to the suppression of pro-inflammatory changes in the arterial wall. We used microarray analyses of total RNA from MEK5/CA-transduced HDMECs compared to LacZ control-transduced HDMECs to identify distinct classes of several regulated genes, including KLF4, eNOS, and ICAM. We conclude that MEK5 activation by shear stress may modulate inflammatory responses in the microvasculature, and these actions are partly mediated by KLF4.
2010-12-31 | GSE25145 | GEO
Project description:Targeted deletion of TRAF7 revealed that it is a crucial part of shear stress-responsive MEKK3-MEK5-ERK5 signaling pathway induced in endothelial cells by blood flow. Similarly, to Mekk3-, Mek5- or Erk5-deficient mice, Traf7-deficient embryos died in utero around midgestation due to impaired endothelial cell integrity. They displayed significantly lower expression of transcription factor Klf2, an essential regulator of vascular hemodynamic forces downstream of the MEKK3-MEK-ERK5 signaling pathway. Deletion of Traf7 in endothelial cells of postnatal mice was also associated with severe cerebral hemorrhage. Here, we show that besides MEKK3 and MEK5, TRAF7 associates with a planar cell polarity protein SCRIB. SCRIB binds with an N-terminal region of TRAF7, while MEKK3 associates with the C-terminal WD40 domain. Downregulation of TRAF7 as well as SCRIB inhibited fluid shear stress-induced phosphorylation of ERK5 in cultured endothelial cells. These findings suggest that TRAF7 and SCRIB may comprise an upstream part of the MEKK3-MEK5-ERK5 signaling pathway. Objective: to present first in vivo experimental evidence of TRAF7 function by using global and endothelium-specific TRAF7 knockout mice and comparing transcriptomes of developing embryos.
2023-06-01 | GSE229698 | GEO
Project description:Mitogen/extracellular signal-regulated kinase kinase-5 (MEK5) belongs to the family of MAP kinases. It is activated by the upstream kinases MEKK2 and MEKK3. MEK5, in turn, phosphorylates and activates extracellular signal-regulated kinase 5 (ERK5) at Thr218/Tyr220. MEK5/ERK5 pathway plays a pivotal role in tumor initiation and progression, including prostate cancer. MEK5 protein is overexpressed in prostate cancer cells compared with normal cells and MEK5 levels are correlated with prostate cancer metastasis. Global gene expression was determined in PC3 cells stably expressing a scrambled (control) shRNA or MEK5 shRNA using the Agilent Mouse Whole Genome microarrays. Gene ontology and pathway analysis of differentially expressed genes using Ingenuity Pathway Analysis and gene set enrichment analysis (GSEA) revealed MEK5 knockdown attenuates a number or critical signaling pathways required for prostate tumor growth and progression.
2023-08-16 | GSE156401 | GEO
Project description:Mitogen/extracellular signal-regulated kinase kinase-5 (MEK5) belongs to the family of MAP kinases. It is activated by the upstream kinases MEKK2 and MEKK3. MEK5, in turn, phosphorylates and activates extracellular signal-regulated kinase 5 (ERK5) at Thr218/Tyr220. MEK5/ERK5 pathway plays a pivotal role in tumor initiation and progression, including prostate cancer. MEK5 protein is overexpressed in prostate cancer cells compared with normal cells and MEK5 levels are correlated with prostate cancer metastasis. Global gene expression was determined in DU145 cells stably expressing a scrambled (control) shRNA or MEK5 shRNA using the Agilent Mouse Whole Genome microarrays. Gene ontology and pathway analysis of differentially expressed genes using Ingenuity Pathway Analysis and gene set enrichment analysis (GSEA) revealed MEK5 knockdown attenuates a number or critical signaling pathways required for prostate tumor growth and progression.
2023-08-16 | GSE156399 | GEO
Project description:RAS/RAF/MEK/ERK1/2 MAPK pathway-based treatments, typically combination therapies with inhibitors for oncogenic BRAF V600 (BRAFi) and MEK1/2 (MEKi), are important treatment alternatives to immunotherapy in advanced BRAF-mutated melanoma. However, their benefit is limited by frequent therapy resistance, i.e. persistence and tumor progression/metastasis under sustained treatment. Furthermore, approximately 50% of the patients, including the NRAS-mutated subset, lack targetable BRAF oncogenes and profit poorly from MEKi. Recent preclinical studies suggest that co-inhibition of the MEK5/ERK5 MAPK pathway, which in different MAPK-activated tumors is compensatorily activated by MEKi, represents a promising strategy to overcome therapy resistance and trigger apoptosis and/or sustained cell cycle arrest. In NRAS-mutant melanoma compensatory ERK5 activation is accompanied by the induction of the two Krüppel-like factors KLF2 and KLF4 Their functional relevance in MEKi resistance, however,is unclear. Using siRNA and CRISPR/Cas9, we examined their contribution to MEKi resistance through functional assays and RNA sequencing. Surprisingly, KLF2 and KLF4 were dispensable for the proliferative and anti-apoptotic effects of compensatory ERK5 activation in MEKi-exposed melanoma. Instead, we identified AXL, a key receptor tyrosine kinase associated with metastasis and phenotypic switching, as critical ERK5/KLF4 target induced during MEKi resistance and demonstrate that KLF4 loss or AXL depletion results in reduced melanoma cell migration and invasion. Our study describes a novel ERK5/KLF4/AXL signaling axis that drives MEKi resistance and metastatic potential in NRAS-mutant melanoma. Targeting this pathway may enhance the efficacy of MAPK-directed therapies and potentially improve responses to immune therapy, where AXL expression similarly promotes tumor progression.
2026-04-01 | GSE319305 | GEO
Project description:We have employed a high-content microscopy screen in combination with a kinome and phosphatome-wide siRNA library to identify signaling pathways underlying an EMT of murine mammary epithelial cells and breast cancer cells. This screen identified the MEK5-ERK5 axis as a critical player in TGFb-mediated EMT. Suppression of MEK5-ERK5 signaling completely prevented the morphological and molecular changes occurring during a TGFb-induced EMT and, conversely, forced highly metastatic breast cancer cells into a differentiated epithelial state. Inhibition of MEK5-ERK5 signaling also repressed breast cancer cell migration and invasion and substantially reduced lung metastasis without affecting primary tumor growth. The results suggest that the MEK5-ERK5 signaling axis plays an important role in the induction and maintenance of breast cancer cell migration and invasion and thus represents an exploitable target for the pharmacological inhibition of cancer cell metastasis.
2018-05-17 | GSE100403 | GEO
Project description:To investigate the function of MEK5/ERK5 in the regulation of hPSC pluripotency, we processed MAP2K5DD (MEK5DD) overexpression H1 ESC line.
2024-03-01 | GSE234056 | GEO
Project description:Vascular endothelial cells (ECs) encode a homeostatic fluid shear stress (FSS) set point that is essential for vascular stability. Deviations above or below this threshold trigger adaptive remodeling to restore physiological shear levels. Disruption of this control mechanism leads to enlarged arterial-venous malformations (AVMs) in hereditary haemorrhagic telangiectasia (HHT), a vascular disorder caused by heterozygous loss-of-function (LOF) mutation in ALK1, ENG or SMAD4. Mechanistically, Smad4 deficient ECs are reset to a lower FSS set point value, resulting in AVMs that show characteristics of high FSS remodeling with elevated Klf4 and excessive activation of the downstream Akt. Here, we investigated the Klf4-Akt upstream mechanisms by which Smad4 sets the physiological FSS setpoint. We identified the receptor tyrosine kinase c-Kit as a novel component and regulator of the junctional mechanosensory receptor complex, which is highly upregulated in murine and human AVMs. Smad4 restrains flow signaling by limiting c-Kit-dependent Erk5 activation and Klf4 induction. Thus, Smad4 LOF leads to sustained c-Kit engagement in the sensory junctional apparatus, driving excessive and prolonged activation of the Erk5-Klf4-Akt signaling axis. These results show that Smad4 LOF mutations induce malformations by disabling a key homeostatic mechanism and identify c-Kit as a novel therapeutic target.
2026-05-11 | GSE330070 | GEO
Project description:We expressed a constitutively active mutant of MEK5 (MEK5D) in human primary endothelial cells (EC) to study the transcriptional and functional responses to Erk5 activation under static conditions.
2010-06-16 | GSE17939 | GEO