Similar Datasets
Project description:Effect of DNA damage on ligand stimulated EGFR signaling pathways
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Project description:Selection of activating EGFR mutations from randomly mutated EGFR libraries
| PRJEB49811 | ENA
Project description:Despite extensive study of the epidermal growth factor receptor (EGFR) signaling network, the immediate post-translational changes that occur in response to growth factor stimulation remain poorly characterized; as a result, the biological mechanisms underlying signaling initiation remain obscured. To address this deficiency, we have used a mass spectrometry-based approach to measure system-wide phosphorylation changes throughout the network with 10 second resolution in the 80 seconds after stimulation in response to a range of 8 growth factor concentrations. Significant changes were observed on proteins far downstream in the network as early as 10 seconds after stimulation, indicating a system capable of transmitting information quickly. Meanwhile, canonical members of the EGFR signaling network fall into clusters with distinct activation patterns. Shc and PI3K phosphorylation levels increase rapidly, but equilibrate within 20 s, while proteins like Gab1 and SHP2 show slower, sustained increases. Proximity ligation assays reveal that Shc and Gab1 phosphorylation patterns are representative of separate timescales for physical association with the receptor. Inhibition of phosphatases with vanadate reveals site-specific regulatory mechanisms, and also uncovers primed activating components in the network, including Src family kinases, whose inhibition impacts only a subset of proteins within the network. The results presented highlight the complexity of signaling initiation, and provide a window into exploring mechanistic hypotheses about RTK biology.
2017-03-29 | MSV000080800 | MassIVE
Project description:Despite extensive study of the epidermal growth factor receptor (EGFR) signaling network, the immediate post-translational changes that occur in response to growth factor stimulation remain poorly characterized; as a result, the biological mechanisms underlying signaling initiation remain obscured. To address this deficiency, we have used a mass spectrometry-based approach to measure system-wide phosphorylation changes throughout the network with 10 second resolution in the 80 seconds after stimulation in response to a range of 8 growth factor concentrations. Significant changes were observed on proteins far downstream in the network as early as 10 seconds after stimulation, indicating a system capable of transmitting information quickly. Meanwhile, canonical members of the EGFR signaling network fall into clusters with distinct activation patterns. Shc and PI3K phosphorylation levels increase rapidly, but equilibrate within 20 s, while proteins like Gab1 and SHP2 show slower, sustained increases. Proximity ligation assays reveal that Shc and Gab1 phosphorylation patterns are representative of separate timescales for physical association with the receptor. Inhibition of phosphatases with vanadate reveals site-specific regulatory mechanisms, and also uncovers primed activating components in the network, including Src family kinases, whose inhibition impacts only a subset of proteins within the network. The results presented highlight the complexity of signaling initiation, and provide a window into exploring mechanistic hypotheses about RTK biology.
2016-06-24 | PXD003660 | Pride
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:Kholodenko1999 - EGFR signaling
This model has been generated by the JWS Online project by Jacky Snoep using PySCeS
Run this model online at http://jjj.biochem.sun.ac.za
To cite JWS Online please refer to: Olivier, B.G. and Snoep, J.L. (2004) Web-based
modelling using JWS Online
, Bioinformatics, 20:2143-2144
This model is described in the article:
Quantification of short term signaling by the epidermal growth factor receptor.
Kholodenko BN, Demin OV, Moehren G, Hoek JB
J. Biol. Chem. 1999 Oct; 274(42): 30169-30181
Abstract:
During the past decade, our knowledge of molecular mechanisms involved in growth factor signaling has proliferated almost explosively. However, the kinetics and control of information transfer through signaling networks remain poorly understood. This paper combines experimental kinetic analysis and computational modeling of the short term pattern of cellular responses to epidermal growth factor (EGF) in isolated hepatocytes. The experimental data show transient tyrosine phosphorylation of the EGF receptor (EGFR) and transient or sustained response patterns in multiple signaling proteins targeted by EGFR. Transient responses exhibit pronounced maxima, reached within 15-30 s of EGF stimulation and followed by a decline to relatively low (quasi-steady-state) levels. In contrast to earlier suggestions, we demonstrate that the experimentally observed transients can be accounted for without requiring receptor-mediated activation of specific tyrosine phosphatases, following EGF stimulation. The kinetic model predicts how the cellular response is controlled by the relative levels and activity states of signaling proteins and under what conditions activation patterns are transient or sustained. EGFR signaling patterns appear to be robust with respect to variations in many elemental rate constants within the range of experimentally measured values. On the other hand, we specify which changes in the kinetic scheme, rate constants, and total amounts of molecular factors involved are incompatible with the experimentally observed kinetics of signal transfer. Quantitation of signaling network responses to growth factors allows us to assess how cells process information controlling their growth and differentiation.
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2024-09-02 | BIOMD0000000048 | BioModels
Project description:MCF10A cells derived from spontaneously immortalized normal human mammary epithelia were subjected to EGF/SERUM stimulation for 0,20,40,60,120,240 and 480 minutes. We used microarrays to understand the temporal regulation of the cellular EGFR cascade. Experiment Overall Design: MCF10A cells were grown in DME:F12 medium supplemented with antibiotics, [10 mg/ml insulin, 0.1 mg/ml cholera toxin, 0.5 mg/ml hydrocortisone, heat-inactivated horse serum (5%); defined as 'serum' in the text] and 10ng/ml EGF. Cells were serum deprived for 24 hours. Following stimulation with EGF/SERUM for 0,20,40,60,120,240 and 480 minutes.
2007-11-01 | E-GEOD-6784 | biostudies-arrayexpress
Project description:EGFR tyrosine kinase inhibitors cause dramatic responses in EGFR-mutant lung cancer, but resistance universally develops. The involvement of β-catenin in EGFR TKI resistance has been previously reported however the precise mechanism by which β-catenin activation contributes to EGFR TKI resistance is not clear. Here, we show that EGFR inhibition results in the activation of β-catenin signaling in a Notch3-dependent manner, which facilitates the survival of a subset of cells that we call “adaptive persisters”. We previously reported that EGFR-TKI treatment rapidly activates Notch3, and here describe the physical association of Notch3 with β-catenin, leading to increased stability and activation of β-catenin. We demonstrate that the combination of EGFR-TKI and a β-catenin inhibitor inhibits the development of these adaptive persisters, decreases tumor burden, improves recurrence free survival, and overall survival in xenograft models. These results supports combined EGFR-TKI and β-catenin inhibition in patients with EGFR mutant lung cancer.
2018-08-31 | GSE115864 | GEO
Project description:The Epidermal Growth Factor Receptor (EGFR) has been studied extensively due to its critical role in cellular signaling and association with disease. Previous models have elucidated interactions between EGFR and downstream adaptor proteins, or showed phenotypes affected by EGFR. However, the link between EGFR phosphorylation and phenotypic outcome is still poorly understood. Here, we employed a suite of isogenic cells lines expressing site-specific mutations at each of the EGFR C-terminal phosphorylation sites to interrogate their role in signaling network and cell biological response to stimulation. Our results demonstrate the resilience of the EGFR network, which was largely similar even in the context of multiple Y-to-F mutations in the EGFR C-terminal tail, while also revealing nodes in the network that have not previously been linked to EGFR signaling. Our data-driven model highlights signaling network nodes associated with distinct EGF-driven cell responses, including migration, proliferation, and receptor trafficking. Application of this same approach to less studied RTKs should provide a plethora of novel associations that should lead to a much better understanding of these signaling networks.
2023-05-09 | PXD032403 | Pride
Project description:The clinical efficacy of EGFR kinase inhibitors is limited by the development of drug resistance. The irreversible EGFR kinase inhibitor WZ4002 is effective against the most common mechanism of drug resistance mediated by the EGFR T790M mutation. Here we show that in multiple complementary models harboring EGFR T790M, resistance to WZ4002 develops through aberrant activation of ERK signaling caused by either an amplification of MAPK1 or by downregulation of negative regulators of ERK signaling. Inhibition of MEK or ERK restores sensitivity to WZ4002, and the combination of WZ4002 and a MEK inhibitor prevents the emergence of drug resistance. The WZ4002 resistant MAPK1 amplified cells also demonstrate an increase both in EGFR internalization and a decrease in sensitivity to cytotoxic chemotherapy compared to the parental counterparts. Our findings provide insights into mechanisms of drug resistance to EGFR kinase inhibitors and highlight rational combination therapies that should be evaluated in clinical trials. Our study identifies ERK signaling as a mediator of resistance to irreversible pyrimidine EGFR inhibitors in EGFR T790M-bearing cancers. We further provide a therapeutic strategy to both treat and prevent the emergence of this resistance mechanism. To generate drug-resistant NCI-H1975 cell lines, non-small cell lung cancer (NSCLC) cells were exposed to increasing concentrations of WZ4002 similar to previously described methods. Individual clones from WZ4002-resistant (WZR) cells were isolated and confirmed to be drug resistant. Clone #6, designated as WZR6, was used in this study. For expression analysis, samples were prepared in triplicate from parental NCI-H1975 and NCI-H1975 WZR6 cells.
2012-10-01 | E-GEOD-37699 | biostudies-arrayexpress