Cavin-3 Dictates the Balance Between ERK and Akt Signaling
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Peter Michaely
PROVIDER: E-GEOD-50982 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:Cavin-3 is a tumor suppressor protein of unknown function. Using a combination of in vivo knockout and in vitro gain/loss of function approaches, we show that cavin-3 dictates the balance between ERK and Akt signaling. Loss of cavin-3 increases Akt signaling at the expense of ERK, while gain of cavin-3 increases ERK signaling at the expense Akt. Cavin-3 facilitates signal transduction to ERK by anchoring caveolae, a lipid-raft specialization that contains an ERK activation module, to the membrane skeleton of the plasma membrane. Loss of cavin-3 reduces the number of caveolae, thereby separating this ERK activation module from signaling receptors. Loss of cavin-3 promotes Akt signaling through suppression of EGR1 and PTEN. The in vitro consequences of the loss of cavin-3 include induction of Warburg metabolism (aerobic glycolysis), accelerated cell proliferation and resistance to apoptosis. The in vivo consequences of cavin-3 loss are increased lactate production and cachexia.
2013-09-24 | GSE50982 | GEO
Project description:FGFR signaling plays important roles in development and disease pathogenesis. FGFR activation initiates phosphorylation-driven signaling cascades, most notably the RAS-RAF-MEK-ERK cascade and the PI3K-AKT cascade. PTEN antagonizes FGFR signaling by reducing both AKT and ERK activation. Lenses lacking FGFR2 exhibit lower levels of ERK and AKT phosphorylation accompanied by abnormally small lenses, widespread apoptosis, and defective fiber cell differentiation. In contrast, simultaneous deletion of both Fgfr2 and Pten restores ERK and AKT activation levels as well as lens size, cell survival and several aspects of fiber cell differentiation. A transcriptomic analysis of mouse lenses lacking Fgfr2, Pten or both Fgfr2 and Pten revealed molecular mechanisms that might explain how FGFR2 and PTEN signaling interact during development. The FGFR2-deficient lens transcriptome suggested an overall loss of fiber cell identity with deregulated expression of 1,448 genes, nearly 60% of which returned to normal expression levels in lenses lacking both Fgfr2 and Pten. A specific set of parameters based on expression levels in each genotype identified 68 high priority candidate genes. The homeobox transcription factor, NKX6-1, encoded by one of these genes, had at least one binding motif in the putative promoters of 53 of these 68 genes. Furthermore, NKX6-1 activated the expression of the high priority candidate Rasgrp1, a RAS-activating guanine nucleotide exchange factor. Together, these data suggest a novel regulatory module in which NKX6-1 activates the expression of Rasgrp1 to restore the balance of ERK and AKT activation in the absence of both FGFR2 and PTEN.
2020-02-28 | GSE132945 | GEO
Project description:Dataset containing multiple Hyptis and Artemisia spp. used for the discovery of natural products inhibiting aberrant signaling, namely MAPK/ERK and PI3K/AKT, in melanoma
2021-12-22 | MSV000088606 | GNPS
Project description:Bidkhori2012 - EGFR signalling in NSCLC
The paper describes and compares two models on EGFR signalling between normal and NSCLC cells. Moreover, it is shown that ERK (MAPK), STAT and Akt factor's activation pattern are different between normal and NSCLA models. This model corresponds to EGFR signalling in NSCLA cells.
Created by The MathWorks, Inc. SimBiology tool, Version 3.3
This model is described in the article:
Modeling of tumor progression in NSCLC and intrinsic resistance to TKI in loss of PTEN expression.
Bidkhori G, Moeini A, Masoudi-Nejad A
PloS one [2012, 7(10):e48004]
Abstract:
EGFR signaling plays a very important role in NSCLC. It activates Ras/ERK, PI3K/Akt and STAT activation pathways. These are the main pathways for cell proliferation and survival. We have developed two mathematical models to relate to the different EGFR signaling in NSCLC and normal cells in the presence or absence of EGFR and PTEN mutations. The dynamics of downstream signaling pathways vary in the disease state and activation of some factors can be indicative of drug resistance. Our simulation denotes the effect of EGFR mutations and increased expression of certain factors in NSCLC EGFR signaling on each of the three pathways where levels of pERK, pSTAT and pAkt are increased. Over activation of ERK, Akt and STAT3 which are the main cell proliferation and survival factors act as promoting factors for tumor progression in NSCLC. In case of loss of PTEN, Akt activity level is considerably increased. Our simulation results show that in the presence of erlotinib, downstream factors i.e. pAkt, pSTAT3 and pERK are inhibited. However, in case of loss of PTEN expression in the presence of erlotinib, pAkt level would not decrease which demonstrates that these cells are resistant to erlotinib.
This model is hosted on BioModels Database
and identified
by: MODEL1304020001
.
To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource
for published quantitative kinetic models
.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to the public
domain worldwide. Please refer to CC0 Public Domain
Dedication
for more information.
2013-05-13 | BIOMD0000000453 | BioModels
Project description:Bidkhori2012 - normal EGFR signalling
The paper describes and compares two models on EGFR signalling between normal and NSCLC cells. Moreover, it is shown that ERK (MAPK), STAT and Akt factor's activation pattern are different between normal and NSCLA models. This model corresponds to EGFR signalling in normal cells.
Created by The MathWorks, Inc. SimBiology tool, Version 3.3
This model is described in the article:
Modeling of tumor progression in NSCLC and intrinsic resistance to TKI in loss of PTEN expression.
Bidkhori G, Moeini A, Masoudi-Nejad A
PloS one [2012, 7(10):e48004]
Abstract:
EGFR signaling plays a very important role in NSCLC. It activates Ras/ERK, PI3K/Akt and STAT activation pathways. These are the main pathways for cell proliferation and survival. We have developed two mathematical models to relate to the different EGFR signaling in NSCLC and normal cells in the presence or absence of EGFR and PTEN mutations. The dynamics of downstream signaling pathways vary in the disease state and activation of some factors can be indicative of drug resistance. Our simulation denotes the effect of EGFR mutations and increased expression of certain factors in NSCLC EGFR signaling on each of the three pathways where levels of pERK, pSTAT and pAkt are increased. Over activation of ERK, Akt and STAT3 which are the main cell proliferation and survival factors act as promoting factors for tumor progression in NSCLC. In case of loss of PTEN, Akt activity level is considerably increased. Our simulation results show that in the presence of erlotinib, downstream factors i.e. pAkt, pSTAT3 and pERK are inhibited. However, in case of loss of PTEN expression in the presence of erlotinib, pAkt level would not decrease which demonstrates that these cells are resistant to erlotinib.
This model is hosted on BioModels Database
and identified
by: MODEL1304020000
.
To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource
for published quantitative kinetic models
.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to the public
domain worldwide. Please refer to CC0 Public Domain
Dedication
for more information.
2013-05-13 | BIOMD0000000452 | BioModels
Project description:Signaling through the AKT and ERK pathways controls cell proliferation. However, the integrated regulation of this multistep process, involving signal processing, cell growth and cell-cycle progression, is poorly understood. Here we study different murine hematopoietic cell types, in which AKT and ERK signaling is triggered by erythropoietin (Epo). Although these cell types share the molecular network topology for pro-proliferative Epo signaling, they exhibit distinct proliferative responses. Iterating quantitative experiments and mathematical modeling, we identify two molecular sources for cell-type-specific proliferation. First, cell-type-specific protein abundance patterns cause differential signal flow along the AKT and ERK pathways. Second, downstream regulators of both pathways have differential effects on proliferation, suggesting that protein synthesis is rate-limiting for faster-cycling cells while slower cell-cycles are controlled at the G1-S progression. The integrated mathematical model of Epo-driven proliferation explains cell-type-specific effects of targeted AKT and ERK inhibitors and faithfully predicts based on the protein abundance anti-proliferative effects of inhibitors in primary human erythroid progenitor cells. Our findings suggest that the effectiveness of targeted cancer therapy might become predictable from protein abundance patterns.
2017-03-31 | MSV000080844 | MassIVE
Project description:Activation of the AKT and ERK signaling pathway is a major contributor to cell proliferation. However, the integrated regulation of this multistep process, involving signal processing, cell growth and cell-cycle progression, is poorly understood. Here we study three cell types of hematopoietic origin, in which AKT and ERK signaling is triggered by erythropoietin (Epo). We find that the different cell types exhibit distinct proliferative responses, despite sharing the molecular network for pro-proliferative signaling. Iterating quantitative experiments and mathematical modeling, we show that the cell-type-specific regulation of proliferation emerges from two sources: (1) the protein abundance patterns of signaling components that cause differential flow of signals along the AKT and ERK pathways, and (2) the differential impact of the downstream regulators for protein synthesis and for cell-cycle progression on proliferation. Our integrated mathematical model of Epo-driven proliferation explains cell-type-specific effects of targeted AKT and ERK inhibitors and correctly predicts whether their combined application results in synergy.
2017-01-20 | GSE72317 | GEO
Project description:Cavin-3 Dictates the Balance Between ERK and Akt Signaling
| PRJNA219476 | ENA
Project description:Amplification and activation of the Met receptor tyrosine kinase occurs up to 23% of gastric cancers, suggesting that Met is a therapeutic target in these cancers. However, the steady-state signaling events that occur during chronic Met activation, and mechanisms for resistance to Met small-molecule inhibitors, are poorly understood. Here we show that multiple gastric cancer cell lines harboring MET amplifications are dependent on Met signaling for proliferation and anchorage-independent growth. In these cells, short-term inhibition of Met leads to coordinated changes in gene expression; these include a rapid loss in expression of immediate-early genes, followed by decreased expression of genes involved in cell cycle and proliferation. Activation of Ras-Erk, PI3K-Akt and STAT3 pathways is attenuated by acute Met inhibition. STAT3 inhibition alone, but not individual inhibition of Mek or Akt, is sufficient to abrogate Met-dependent growth of these cells. However, following chronic Met inhibition, reactivation of Mek-dependent Erk phosphorylation occurs even in the presence of Met inhibitor corresponding with a downregulation of Erk negative regulators DUSP4/6. This provides a mechanism for the emergence of drug resistance. Our findings provide insights into innate resistance to a small-molecule Met inhibitor and highlight rational combination therapies that could be evaluated in clinical trials. Time series experiment, four cell lines, 2 treatments
2014-05-19 | E-GEOD-54532 | biostudies-arrayexpress
Project description:Signaling through the AKT and ERK pathways controls cell proliferation. However, the integrated regulation of this multistep process, involving signal processing, cell growth and cell-cycle progression, is poorly understood. Here we study different murine hematopoietic cell types, in which AKT and ERK signaling is triggered by erythropoietin (Epo). Although these cell types share the molecular network topology for pro-proliferative Epo signaling, they exhibit distinct proliferative responses. Iterating quantitative experiments and mathematical modeling, we identify two molecular sources for cell-type-specific proliferation. First, cell-type-specific protein abundance patterns cause differential signal flow along the AKT and ERK pathways. Second, downstream regulators of both pathways have differential effects on proliferation, suggesting that protein synthesis is rate-limiting for faster-cycling cells while slower cell-cycles are controlled at the G1-S progression. The integrated mathematical model of Epo-driven proliferation explains cell-type-specific effects of targeted AKT and ERK inhibitors and faithfully predicts based on the protein abundance anti-proliferative effects of inhibitors in primary human erythroid progenitor cells. Our findings suggest that the effectiveness of targeted cancer therapy might become predictable from protein abundance patterns.
2017-01-30 | PXD004816 | Pride