The network response to Egf is tissue-specific
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Orbitrap Eclipse, Orbitrap Fusion Lumos
ORGANISM(S): Mus Musculus (mouse)
TISSUE(S): Heart, Lung, Liver, Kidney
SUBMITTER: 
Joao Paulo
LAB HEAD: Kevin M. Haigis
PROVIDER: PXD050402 | Pride | 2025-03-08
REPOSITORIES: Pride
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| 2024-03-06_Beatrice.xlsx | Xlsx | |||
| a28951_20230115131515.raw | Raw | |||
| a28951_20230115131515_bea_mou_pho3.mzIdentML | Mzid | |||
| a28952_20230115161242.raw | Raw | |||
| a28952_20230115161242_bea_mou_pho3.mzIdentML | Mzid |
Items per page: 5 1 - 5 of 197 |
Similar Datasets
Project description:Epidermal growth factor receptor (EGFR)-driven signaling regulates fundamental cellular processes. Dysregulated signaling via EGFR is implicated in numerous disease pathologies, and distinct EGFR-associated disease etiologies are known to be tissue-specific. The molecular basis of this tissue specificity remains poorly understood. Most studies of EGFR signaling to date have been performed in vitro or in tissue-specific mouse models of disease, which has limited insight into EGFR signaling patterns in healthy tissues. Here, we carried out integrated phosphoproteomic, proteomic, and transcriptomic analyses of signaling changes across various mouse tissues in response to short-term stimulation with the Egfr ligand Egf. We show how both baseline and Egf-stimulated signaling behaviors differ between tissues. Moreover, we propose how baseline phosphorylation and total protein levels may be associated with clinically relevant tissue-specific Egfr-associated phenotypes. Altogether, our analyses illustrate tissue-specific effects of Egf stimulation and highlight potential links between underlying tissue biology and Egfr signaling output.
2025-03-06 | GSE262676 | GEO
Project description:Aberrant activation of Hedgehog (HH) signaling has been identified as a key etiologic factor of many human malignancies. Signal strength, target gene specificity, and oncogenic activity of HH signaling profoundly depend on interactions with other pathways such as epidermal growth factor receptor-mediated signaling which has been shown to cooperate with HH/GLI in basal cell carcinoma and pancreatic cancer. We demonstrate that the human medulloblastoma cell line Daoy possesses a fully inducible endogenous HH pathway. Treatment of Daoy cells with Sonic Hedgehog or Smoothened agonist induced expression of GLI1 protein and prevented processing of GLI3 to its repressor form. To study interactions between HH- and EGF-induced signaling in greater detail, time-resolved measurements were carried out and analyzed on the transcriptomic as well as proteomic level. Daoy cells responded to the co-treatment by downregulating GLI1, PTCH, and HHIP on the transcript level which was also seen when Amphiregulin (AREG) was used instead of EGF. The finding that EGFR signaling silences proteins acting as negative regulators of HH signaling is firstly described here as a novel crosstalk mechanism. Furthermore, combined EGFR/HH signaling maintains high GLI1 protein levels contrasting its downregulation on the transcript level. On the other hand, high level synergism was observed with respect to a strong and significant upregulation of numerous canonical EGF-targets with putative tumor-promoting properties such as MMP7, VEGFA, and IL-8. In conclusion, synergistic effects between EGFR and HH signaling can selectively induce a switch from a canonical HH/GLI profile to a modulated specific target gene profile pointing to more wide-spread, yet context-dependent, interactions between HH/GLI and growth factor receptor signaling in human malignancies. To study interactions between HH- and EGF-induced signaling, time-resolved measurements were carried out over a period of 24 h at 14 different time points after stimulation by EGF with and without additional stimulation by SHH. Furthermore, as a control, cells without any stimulation by EGF and SHH (control) and cells in the presents of SHH were analyzed. Overall, three biological replicates of 60 different treatment/timepoints were analyzed yielding 180 different samples.
2014-07-31 | E-GEOD-46045 | biostudies-arrayexpress
Project description:Epidermal growth factor receptor (EGFR) signaling is frequently dysregulated in a variety of cancers. The ubiquitin ligase Cbl regulates degradation of activated EGFR through ubiquitination and acts as an adaptor to recruit proteins required for trafficking. We used Stable Isotope Labeling with Amino Acids in Cell Culture (SILAC) mass spectrometry (MS) to compare Cbl complexes in the absence and presence of EGF stimulation. We identified over a hundred novel Cbl interactors, and a secondary siRNA screen found that knockdown of Flotillin-2 (FLOT2) led to increased phosphorylation and degradation of EGFR upon EGF stimulation in HeLa cells. In H441 cells, FLOT2 knockdown increased EGF-stimulated EGFR phosphorylation, ubiquitination, and downstream signaling, reversible by the EGFR inhibitor erlotinib. CRISPR knockout of FLOT2 in HeLa cells confirmed EGFR downregulation, increased signaling, and increased dimerization and trafficking to the early endosome. FLOT2 interacts with both Cbl and EGFR. Downregulation of EGFR upon FLOT2 loss is Cbl-dependent, as co-knockdown of Cbl and Cbl-b restored EGFR levels. Stable overexpression of FLOT2 in HeLa cells decreased EGF-stimulated EGFR phosphorylation and ubiquitination. Overexpression of wild type (WT) FLOT2, but not the soluble G2A FLOT2 mutant, inhibited EGFR phosphorylation upon EGF stimulation in HEK293T cells. FLOT2 loss induces EGFR-dependent proliferation and anchorage-independent cell growth. Lastly, FLOT2 knockout increases tumor formation and tumor volume in nude mice and NSG mice, respectively. These data demonstrate that FLOT2 negatively regulates EGFR activation and dimerization, as well as its subsequent ubiquitination, endosomal trafficking, and degradation. FLOT2 negatively regulates proliferation in vitro and in vivo.
2023-03-11 | PXD031988 | Pride
Project description:Clear cell renal cell carcinoma (ccRCC) is the most common variant of kidney cancer in the adult population. Late diagnosis, resistance to therapeutics and recurrence of metastatic lesions account for the highest mortality rate among kidney cancer patients. Identifying novel biomarkers for early cancer detection and the mechanisms underlying ccRCC growth and progression will provide clues to treat this aggressive malignant tumor. Here, we report that the RING ligase praja2 is a novel component of the endocytic system that supports clathrin-mediated receptor endocytosis. At molecular level, we identify the adaptor protein AP2 as a binding partner and substrate of praja2. Functionally, we demonstrate that praja2 is required for AP2-mediated receptor endocytosis and clearance. Downregulation of praja2 in RCC cells and tissues is associated with a marked upregulation of membrane receptors, as EGFR, VEGFR and TfR. A negative feedback loop links EGF signaling to proteolysis of praja2 and sustains downstream mitogenic and proliferative pathways. Restoring praja2 expression in RCC cells remarkably decreases EGFR levels, rewires cancer cell metabolism and inhibits RCC growth and metastatic diffusion. In praja2 knockout mice, upregulation of RTKs levels associates with profound histopathological renal alterations. Our findings identify praja2 as a component of the endocytic pathway that supports receptor endocytosis and clearance. Downregulation of praja2 in RCC cells, thus, sustains RTK signaling and promotes kidney cancer growth and diffusion.
2023-08-13 | E-MTAB-11900 | biostudies-arrayexpress
Project description:Controlled activation of epidermal growth factor receptor (EGFR) is systematically guaranteed at the molecular level, however aberrant activation of EGFR is frequently found in cancer. Transcription induced by EGFR activation often involves coordinated expression of genes that positively and negatively regulate the original signaling pathway, therefore alterations in EGFR kinase activity may reflect changes in gene expression associated with the pathway. In this study, we investigated transcriptional changes following EGF stimulation with or without the EGFR kinase inhibitor Iressa in H1299 human non-small-cell lung cancer cells (parental H1299, H1299 cells which overexpress wild-type: EGFR-WT and mutant EGFR: L858R). Our results clearly showed differences in transcriptional activity in the absence or presence of EGFR kinase activity, and genes sharing the same molecular functions showed distinct expression dynamics. The results showed particular enrichment of EGFR/ErbB signaling-related genes in a differentially expressed gene set, and significant protein expression of MIG6/RALT(ERRFI1), an EGFR negative regulator, was confirmed in L858R. High MIG6 protein expression was correlated with basal EGFR phosphorylation and inversely correlated with EGF-induced ERK phosphorylation levels. Investigation of NCI-60 cell lines showed that ERRFI1 expression was correlated with EGFR expression regardless of tissue type. These results suggest that cells accumulate MIG6 as an inherent negative regulator to suppress excess EGFR activity when basal EGFR kinase activity is considerably high. Taken together, an EGFR mutation can cause transcriptional changes to accommodate the activation potency of the original signaling pathway at the cellular level. Experiment Overall Design: H1299 human non-small cell lung cancer cells were stimulated by the growth hormone (epidermal growth factor (EGF)) or EGFR kinase inhibitor (Iressa). Control was set as non-treated cells.
2009-08-09 | E-GEOD-11729 | biostudies-arrayexpress
Project description:The goal of this experiment is to identify target genes of Egf signaling which regulate recovery of the neoblast population following exposure to a sublethal dose of radiation. A large population of highly proliferative stem cells (neoblasts) is required for physiological tissue homeostasis and regeneration after injury in planarians. Recent studies indicate that survival of a few neoblasts after sublethal irradiation results in the clonal expansion of the surviving stem cells and the eventual restoration of tissue homeostasis and regenerative capacity. Many genes are known to be required for the normal function of neoblasts, but the precise mechanisms regulating the population dynamics of these adult pluripotent stem cells remain largely unknown. By coupling RNAi screening and sublethal irradiation, we uncovered a central role for Epidermal Growth Factor (EGF) signaling during in vivo neoblast expansion mediated by Smed-egfr-3 (egfr-3) and its putative ligand Smed-neuregulin-7 (nrg-7). Furthermore, the EGFR-3 protein localizes asymmetrically on the cytoplasmic membrane of neoblasts and the ratio of asymmetric to symmetric cell divisions decreases significantly in egfr-3(RNAi) worms. Our results not only provide the first molecular evidence of asymmetric stem cell divisions in planarian, but also demonstrate that EGF signaling likely functions as an essential regulator of neoblast clonal expansion.
2016-08-18 | GSE84025 | GEO
Project description:Molecular switches are essential modules in signaling networks by enabling a quick response to environmental changes. Here, we describe a role for small ubiquitin-like-modifier SUMO as a molecular switch in epidermal growth factor receptor (EGFR) signaling. Using quantitative mass spectrometry, we compared the endogenous SUMO-proteomes of Hela cells before and after EGF-stimulation. Thereby, we identified a small group of transcriptional repressors, including IRF2BP1, IRF2BP2 and IRF2BPL as novel players in EGFR signaling, which lost SUMO transiently within 15 min of EGF treatment. We found 38 genes whose expression within the first hour of EGF treatment was altered in cells expressing SUMOylation deficient IRF2BP1, including Dual specific phosphatase 1 (DUSP1), an important feedback regulator of EGFR signalling. We show that IRF2BP1 binds to the proximal promoter of DUSP1, whose activation requires IRF2BP1 deSUMOylation. Thus, the SUMO-dependent molecular switch of IRF2BP1 activity is important to finely tune EGFR signaling
2021-04-13 | PXD018049 | Pride
Project description:Responsiveness of cells to alpha-toxin (Hla) from Staphylococcus aureus appears to occur in a cell-type dependent manner. Here, we compare two human bronchial epithelial cell lines, i.e. Hla-susceptible 16HBE14o- and Hla-resistant S9 cells, by a quantitative multi-omics strategy for a better understanding of Hla-induced cellular programs. Phosphoproteomics revealed a substantial impact on phosphorylation-dependent signaling in both cell models and highlights alterations in signaling pathways associated with cell-cell and cell-matrix contacts as well as the actin cytoskeleton as key features of early rHla-induced effects. Along comparable changes in down-stream activity of major protein kinases significant differences between both models were found upon rHla-treatment including activation of EGFR and MAPK1/3 signaling in S9 and repression in 16HBE14o- cells. System-wide transcript and protein expression profiling indicate induction of an immediate early response in either model. In addition, EGFR and MAPK1/3-mediated changes in gene expression suggest cellular recovery and survival in S9 cells but cell death in 16HBE14o- cells. Strikingly, inhibition of the EGFR sensitized S9 cells to Hla indicating that the cellular capacity of activation of the EGFR is a major protective determinant against Hla-mediated cytotoxic effects. Design includes two different human bronchial epithelial cell lines, one control treatment (mock treatment for 2 hours) and one condition (2 alpha toxin treatment for 2 hours). Experiments for both cell line were replicated twice (biological replication).
2015-03-31 | E-GEOD-65018 | biostudies-arrayexpress
Project description:Lupus nephritis (LN) often results in progressive renal dysfunction. The inactive Rhomboid 2 (iRhom2) is a newly identified key regulator of A disintegrin and metalloprotease 17 (ADAM17), whose substrates, such as TNF-α and heparin-binding EGF (HB-EGF), have been implicated in the pathogenesis of chronic kidney disease. Here we demonstrate that deficiency of iRhom2 protects the lupus-prone Fcgr2b-/- mice from developing severe kidney damage without altering anti-double stranded (ds) DNA Ab production, by simultaneously blocking the HB-EGF/EGFR and the TNF-α signaling in the kidney tissues. Unbiased transcriptome profiling of kidneys and kidney macrophages revealed that TNF-α and HB-EGF/EGFR signaling pathways are highly upregulated in Fcgr2b-/- mice; alterations that were diminished in the absence of iRhom2. Pharmacological blockade of either TNF-α or EGFR signaling protected Fcgr2b-/- mice from severe renal damage. Finally, kidneys from LN patients showed increased iRhom2 and HB-EGF expression, with interstitial HB-EGF expression significantly associated with chronicity indices. Our data suggest that activation of iRhom2/ADAM17-dependent TNF-α and EGFR signaling plays a crucial role in mediating irreversible kidney damage in LN, thereby uncovering a novel target for selective and simultaneous dual inhibition of two major pathological pathways in the effector arm of the disease.
2019-01-01 | GSE107705 | GEO
Project description:Receptor tyrosine kinases (RTK) bind growth factors and are critical for cell proliferation and differentiation. Their dysregulation leads to a loss of growth control, often resulting in cancer. Epidermal growth factor receptor (EGFR) is the prototypic RTK and can bind several ligands exhibiting distinct mitogenic potentials. Whereas the phosphorylation on individual EGFR sites and their roles for downstream signaling have been extensively studied, less is known about ligand-specific ubiquitination events on EGFR, which are crucial for signal attenuation and termination. We used a proteomics-based workflow for absolute quantitation combined with mathematical modelling to unveil potentially decisive ubiquitination events on EGFR from the first 30 seconds to 15 minutes of stimulation. Four ligands were used for stimulation: epidermal growth factor (EGF), heparin-binding-EGF like growth factor, transforming growth factor- and epiregulin. Whereas only little differences in the kinetic profiles of individual ubiquitination sites were observed, the overall amount of modified receptor differed depending on the used ligand, indicating that absolute magnitude of EGFR ubiquitination, and not distinctly regulated ubiquitination sites, is a major determinant for signal attenuation and the subsequent cellular outcomes.
2022-05-31 | PXD019621 | Pride