VEGFR2
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB47233 | ENA |
REPOSITORIES: ENA
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Project description:The project concerns vascular endothelial growth factor (VEGF) signaling, which is dependent on binding of VEGF to VEGF receptor-2 (VEGFR2) and leads to activation of the receptor kinase and autophosphorylation. Previous mouse studies with the VEGFR-2 phosphorylation site mutation Y1212F showed reduced vascular stability. We here investigate with LC-MS proteomics which signal transduction pathway(s) are lost in the mutant by identifying proteins that bind to the Y1212F site.
2019-08-13 | PXD014517 | Pride
Project description:KRAS G12D mutation is a key oncogenic driver in many solid tumors, including pancreatic, gastric, and colorectal cancers. While recent studies have characterized features associated with primary and acquired resistance to KRAS inhibitors, strategies to overcome such resistance, particularly in the context of gastrointestinal cancers, remain underexplored. Here, we have generated nine human gastrointestinal cancer models, including three patient-derived organoids (PDOs), with acquired resistance to the KRAS G12D-selective inhibitor MRTX1133. Using single-cell RNA sequencing analysis, we identified the enrichment of angiogenesis, hypoxia, and epithelial-to-mesenchymal transition (EMT) signatures in the resistant PDO relative to the parental counterpart. Across all resistant models, VEGFA expression and VEGFR2 phosphorylation were uniformly elevated, which were driven by AKT activation and SP1 nuclear translocation. Mechanistic investigations uncovered increased PI3Kγ activity in MRTX1133-resistant models via KRAS/HRAS overexpression and complex formation of KRAS-p110γ with p101. This leads to the formation of an autocrine VEGFA-VEGFR2 signaling loop and EMT induction. Therapeutically, the disruption of VEGFA-VEGFR2 signaling restored MRTX1133 sensitivity and inhibited EMT. Furthermore, cancer-endothelial paracrine signaling amplified angiogenesis, hypoxia, and EMT signatures in cancer cells and simultaneously promoted endothelial cell proliferation, reinforcing an adaptive feedback mechanism. In MRTX1133-resistant tumor xenograft mouse models, a combination of anti-VEGFR2 therapy and MRTX1133 more effectively reduced tumor growth, angiogenesis, and proliferation markers than monotherapy without significant body weight change. These findings establish VEGFA-VEGFR2 signaling by PI3Kγ activation as a key driver of acquired resistance to KRAS G12D inhibition and provide a rationale for combining VEGFA-VEGFR2 inhibition with KRAS blockade in KRAS-mutant cancers.
2025-03-02 | GSE290487 | GEO
Project description:KRAS G12D mutation is a key oncogenic driver in many solid tumors, including pancreatic, gastric, and colorectal cancers. While recent studies have characterized features associated with primary and acquired resistance to KRAS inhibitors, strategies to overcome such resistance, particularly in the context of gastrointestinal cancers, remain underexplored. Here, we have generated nine human gastrointestinal cancer models, including three patient-derived organoids (PDOs), with acquired resistance to the KRAS G12D-selective inhibitor MRTX1133. Using single-cell RNA sequencing analysis, we identified the enrichment of angiogenesis, hypoxia, and epithelial-to-mesenchymal transition (EMT) signatures in the resistant PDO relative to the parental counterpart. Across all resistant models, VEGFA expression and VEGFR2 phosphorylation were uniformly elevated, which were driven by AKT activation and SP1 nuclear translocation. Mechanistic investigations uncovered increased PI3Kγ activity in MRTX1133-resistant models via KRAS/HRAS overexpression and complex formation of KRAS-p110γ with p101. This leads to the formation of an autocrine VEGFA-VEGFR2 signaling loop and EMT induction. Therapeutically, the disruption of VEGFA-VEGFR2 signaling restored MRTX1133 sensitivity and inhibited EMT. Furthermore, cancer-endothelial paracrine signaling amplified angiogenesis, hypoxia, and EMT signatures in cancer cells and simultaneously promoted endothelial cell proliferation, reinforcing an adaptive feedback mechanism. In MRTX1133-resistant tumor xenograft mouse models, a combination of anti-VEGFR2 therapy and MRTX1133 more effectively reduced tumor growth, angiogenesis, and proliferation markers than monotherapy without significant body weight change. These findings establish VEGFA-VEGFR2 signaling by PI3Kγ activation as a key driver of acquired resistance to KRAS G12D inhibition and provide a rationale for combining VEGFA-VEGFR2 inhibition with KRAS blockade in KRAS-mutant cancers.
2025-03-03 | GSE290526 | GEO
Project description:RNA sequencing of lung tissue from transgenic mice in order to investigate the effect of a single tyrosine to phenylalanine exchange in the endothelial receptor VEGFR2 at position Y949. This exchange creates a mouse with unleaky blood vessels which is an advantage in several diseases such as cancer and cardiovascular disease.
2020-06-12 | E-MTAB-9163 | biostudies-arrayexpress
Project description:VEGFR2 Y949F (lung RNAseq - mice)
| PRJEB38638 | ENA
Project description:The main goal of the project was to identify proteins binding to vascular endothelial growth factor receptor 2 (VEGFR2) phosphorylation site Y1173. Synthetic peptides, phosphorylated or not, covering different tyrosine phosphorylation sites in VEGFR2 were immobilized and incubated with cell lysates from human umbilical vein endothelial cells. Retained proteins were analyzed by mass spectrometry. Proteins specifically binding to pY1173 peptide were categorized with regard to the presence of an Src Homology 2 (SH2) domain and the main hits were validated in intact cells treated or not with VEGF, for their ability to bind to the activated wild type VEGFR2 but not to a mutant Y1173F VEGFR2. The role of the pY1173 binding partners in VEGF-regulated endothelial biology was further examined in vitro and in vivo.
2023-09-19 | PXD041024 | Pride
Project description:Vascular endothelial growth factor receptor-2 (VEGFR2) is a key target for regulating the endothelial cell lineage and angiogenesis. It is also expressed by lymphatic endothelial cells (LECs) while its participation in lymphangiogenesis remains inadequately characterized. We demonstrate in this study that VEGFR2 is highly expressed in dermal initial lymphatic vessels and valves. The induced deletion of pan-endothelial Vegfr2 at the neonatal stage produced a potent suppression of dermal lymphatic growth, characterized by a thinner lymphatic diameter, a decreased number of LECs and lymphatic valves. Mechanistically, VEGFR2 insufficiency led to a dramatic decrease in lymphatic VEGFR3, a key regulator mediating signals for lymphatic growth and remodeling. RNA sequencing analysis revealed that GO terms enriched for downregulated genes included biological processes related to EC development while pathways related to hematopoiesis and immune responses were upregulated in the skin of Vegfr2 mutants compared with littermate controls. This was further confirmed by RNA-seq analysis of dermal tissues 48 hours after endothelial Vegfr2 deletion. Consistently, targeting Vegfr2 in PROX1+ cells produced an inhibitory effect on dermal lymphatic growth and recapitulated a similar altered transcriptomic signature. The alteration of lymphatic gene expression was further validated by siRNA-mediated Vegfr2 knockdown in primary LECs, showing a transcriptional trend toward a hematopoietic fate. Findings from this study imply that VEGFR2 is required for the maintenance of endothelial identity, and its insufficiency triggers a transcriptional reprogramming that diminishes VEGFR3-mediated lymphangiogenesis.
2026-08-11 | GSE342725 | GEO
Project description:Vascular endothelial growth factor receptor-2 (VEGFR2) is a key target for regulating the endothelial cell lineage and angiogenesis. It is also expressed by lymphatic endothelial cells (LECs) while its participation in lymphangiogenesis remains inadequately characterized. We demonstrate in this study that VEGFR2 is highly expressed in dermal initial lymphatic vessels and valves. The induced deletion of pan-endothelial Vegfr2 at the neonatal stage produced a potent suppression of dermal lymphatic growth, characterized by a thinner lymphatic diameter, a decreased number of LECs and lymphatic valves. Mechanistically, VEGFR2 insufficiency led to a dramatic decrease in lymphatic VEGFR3, a key regulator mediating signals for lymphatic growth and remodeling. RNA sequencing analysis revealed that GO terms enriched for downregulated genes included biological processes related to EC development while pathways related to hematopoiesis and immune responses were upregulated in the skin of Vegfr2 mutants compared with littermate controls. This was further confirmed by RNA-seq analysis of dermal tissues 48 hours after endothelial Vegfr2 deletion. Consistently, targeting Vegfr2 in PROX1+ cells produced an inhibitory effect on dermal lymphatic growth and recapitulated a similar altered transcriptomic signature. The alteration of lymphatic gene expression was further validated by siRNA-mediated Vegfr2 knockdown in primary LECs, showing a transcriptional trend toward a hematopoietic fate. Findings from this study imply that VEGFR2 is required for the maintenance of endothelial identity, and its insufficiency triggers a transcriptional reprogramming that diminishes VEGFR3-mediated lymphangiogenesis.
2026-08-11 | GSE342723 | GEO
Project description:Vascular endothelial growth factor receptor-2 (VEGFR2) is a key target for regulating the endothelial cell lineage and angiogenesis. It is also expressed by lymphatic endothelial cells (LECs) while its participation in lymphangiogenesis remains inadequately characterized. We demonstrate in this study that VEGFR2 is highly expressed in dermal initial lymphatic vessels and valves. The induced deletion of pan-endothelial Vegfr2 at the neonatal stage produced a potent suppression of dermal lymphatic growth, characterized by a thinner lymphatic diameter, a decreased number of LECs and lymphatic valves. Mechanistically, VEGFR2 insufficiency led to a dramatic decrease in lymphatic VEGFR3, a key regulator mediating signals for lymphatic growth and remodeling. RNA sequencing analysis revealed that GO terms enriched for downregulated genes included biological processes related to EC development while pathways related to hematopoiesis and immune responses were upregulated in the skin of Vegfr2 mutants compared with littermate controls. This was further confirmed by RNA-seq analysis of dermal tissues 48 hours after endothelial Vegfr2 deletion. Consistently, targeting Vegfr2 in PROX1+ cells produced an inhibitory effect on dermal lymphatic growth and recapitulated a similar altered transcriptomic signature. The alteration of lymphatic gene expression was further validated by siRNA-mediated Vegfr2 knockdown in primary LECs, showing a transcriptional trend toward a hematopoietic fate. Findings from this study imply that VEGFR2 is required for the maintenance of endothelial identity, and its insufficiency triggers a transcriptional reprogramming that diminishes VEGFR3-mediated lymphangiogenesis.
2026-08-11 | GSE342716 | GEO