Determining the mechanosensitive targets of ERK and Wnt pathways in embryonic stem cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA516920 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8483390.fastq.gz | Fastqsanger.gz | |||
| SRR8483400.fastq.gz | Fastqsanger.gz | |||
| SRR8483391.fastq.gz | Fastqsanger.gz | |||
| SRR8483401.fastq.gz | Fastqsanger.gz | |||
| SRR8483392.fastq.gz | Fastqsanger.gz |
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Project description:Embryonic stem cells can be maintained in a state of naive pluripotency by the use of 2 inhibitors, PD03 - a MEK inhibitor upstream of ERK, and CHIRON, a GSK3 b inhibitor, which acts as a Wnt agonist. The removal of these inhibitors allow embryonic stem cells to exit pluripotency. To determine if targets of transcriptional targets of these pathways are mechanosensitive such that their activation or suppression would be dependent on mechanical properties of substrate.
2021-08-31 | GSE125615 | GEO
Project description:Kim2007 - Crosstalk between Wnt and ERK pathways
Experimental studies have shown that both Wnt and the MAPK pathways are involved in the pathogenesis of various kinds of cancers (eg. colorectal cancer). The crosstalk between the two pathways have also been identified. Here, Kim et al., (2007) have integrated the experimental evidences on crosstalk mechanisms between the two pathways into a pathway model, and have identified the existence of a hidden positive feedback loop and suggest that this positive feedback loop might participate in the pathogenesis of colorectal cancer.
This model is described in the article:
A hidden oncogenic positive feedback loop caused by crosstalk between Wnt and ERK pathways.
Kim D, Rath O, Kolch W, Cho KH.
Oncogene 2007 Jul; 26(31): 4571-4579
Abstract:
The Wnt and the extracellular signal regulated-kinase (ERK) pathways are both involved in the pathogenesis of various kinds of cancers. Recently, the existence of crosstalk between Wnt and ERK pathways was reported. Gathering all reported results, we have discovered a positive feedback loop embedded in the crosstalk between the Wnt and ERK pathways. We have developed a plausible model that represents the role of this hidden positive feedback loop in the Wnt/ERK pathway crosstalk based on the integration of experimental reports and employing established basic mathematical models of each pathway. Our analysis shows that the positive feedback loop can generate bistability in both the Wnt and ERK signaling pathways, and this prediction was further validated by experiments. In particular, using the commonly accepted assumption that mutations in signaling proteins contribute to cancerogenesis, we have found two conditions through which mutations could evoke an irreversible response leading to a sustained activation of both pathways. One condition is enhanced production of beta-catenin, the other is a reduction of the velocity of MAP kinase phosphatase(s). This enables that high activities of Wnt and ERK pathways are maintained even without a persistent extracellular signal. Thus, our study adds a novel aspect to the molecular mechanisms of carcinogenesis by showing that mutational changes in individual proteins can cause fundamental functional changes well beyond the pathway they function in by a positive feedback loop embedded in crosstalk. Thus, crosstalk between signaling pathways provides a vehicle through which mutations of individual components can affect properties of the system at a larger scale.
Figure 6 of the reference publication has been reproduced. The model as such reproduces the plots corresponding to the normal conditions. To obtain simulations under 1) beta-cataenin mutation; set V12=0.846 (two-fold of the beta-catenin synthetic rate than the normal system. i.e. 2*0.426), 2) PP2A mutation; set Vmax4=Vmax5=33.75 (three-fourths of the PP2A activity that the normal system. i.e. (3/4)*45). The simulation was performed using Copasi 4.10 (Build 55).
This model is hosted on BioModels Database
and identified
by: BIOMD0000000149
.
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.
2024-09-02 | BIOMD0000000149 | BioModels
Project description:Chemotherapy resistance and disease recurrence remains major causes of gastric cancer patient mortality. We describe possible relationship between Wnt/b-catenin and RAS/ERK pathways in GC patients and acquired-resistant GC PDX tumors against FOLFOX, 5-fluorouracil-based chemotherapy. RNA sequencing analysis also demonstrates that Wnt/b-catenin pathway is an actionable target pathway for overcoming the chemotherapy resistance. These provide that an approach targeting both Wnt/b-catenin and RAS/ERK pathways could be novel therapeutic strategy in GC resistant to standard chemotherapy.
2019-05-26 | GSE128967 | GEO
Project description:Hepatocellular carcinoma (HCC) and Hepatoblastoma (HB) are two liver cancers characterized by high gene deregulation, chromosomal rearrangements and typical mutations in genes related to the Wnt/β-catenin (Wnt) pathway. LHX2, a transcriptional factor member of the LIM homeobox gene family, has important functions in embryogenesis, liver development but also tumorigenesis. LHX2 is an oncogene in may solid tumors and leukemia but its role in liver cancer is unknown. To address this question we analyzed the expression of LHX2 in HCC and HB using various transcriptomic datasets and found a strong connection between LHX2 down-regulation and Wnt activation in these two liver cancers. In HB LHX2 downregulation correlated with multiple poor outcome parameters including higher patient age, intermediate- and high-risk tumors and patients’ survival. A forced expression of LHX2 reduced the proliferation, the migration and the survival of hepatoma cells in vitro through the inactivation of MAPK/ERK and Wnt signalings. In vivo, LHX2 impeded the development of tumors in the chick embryo and repressed the Wnt pathway in Xenopus embryo. RNA-sequencing data and bioinformatic analyses confirmed the deregulation of many biological functions and molecular processes associated with cell migration, cell survival and liver carcinogenesis in LHX2-expressing hepatoma cells. At a mechanistic level, LHX2 induced the disassembling of beta-catenin and T-cell factor 4 and the expression of multiple inhibitors of Wnt (e.g. TLE/Groucho) and MAPK/ERK (e.g. DUSPs) pathways. Collectively, our findings demonstrate the tumor suppressive function of LHX2 in adult and pediatric liver cancers.
2023-11-01 | GSE160939 | GEO
Project description:The partial EMT program drives breast cancer stemness and metastasis. This process is governed by transcriptional regulators that maintain the epithelial/mesenchymal (E/M) bipotent stem cell state and by differential growth factor signaling driving self-renewal vs differentiation. Here we show that TCF1/Wnt signaling stimulates transient ERK/CDK4/6 activation which upregulates FOXC2, and in turn TAp63 and ΔNp63 isoforms, thereby maintaining the partial EMT state. In parallel, ERK/CDK4/6 promotes FOXC2 expression and S-phase transition while activating FOXM1 to drive E/M cell self-renewal. Interestingly, transient ERK activation by Wnt3a inactivates EGFR, thus preventing EGF from causing a robust and sustained ERK phosphorylation that causes E/M to M differentiation, resulting in CSC exhaustion. Consistent with these data, ERK/CDK4/6 inhibition suppressed CSC organoid forming ability. Collectively, these findings illustrate an intricate mechanism integrating cancer stemness with self-renewal and differentiation via Wnt-stimulated ERK/CDK4/6 activation, underscoring the implication of these findings for cancer stem cell therapy.
2025-01-01 | GSE274094 | GEO
Project description:Determining ELL2 direct targets via ChIPseq
| PRJNA471339 | ENA
Project description:Padala2017- ERK, PI3K/Akt and Wnt signalling
network (normal)
Crosstalk model of the ERK, Wnt and Akt
signalling pathways under normal condition.
This model is described in the article:
Cancerous perturbations
within the ERK, PI3K/Akt, and Wnt/?-catenin signaling network
constitutively activate inter-pathway positive feedback
loops.
Padala RR, Karnawat R, Viswanathan
SB, Thakkar AV, Das AB.
Mol Biosyst 2017 May; 13(5):
830-840
Abstract:
Perturbations in molecular signaling pathways are a result
of genetic or epigenetic alterations, which may lead to
malignant transformation of cells. Despite cellular robustness,
specific genetic or epigenetic changes of any gene can trigger
a cascade of failures, which result in the malfunctioning of
cell signaling pathways and lead to cancer phenotypes. The
extent of cellular robustness has a link with the architecture
of the network such as feedback and feedforward loops.
Perturbation in components within feedback loops causes a
transition from a regulated to a persistently activated state
and results in uncontrolled cell growth. This work represents
the mathematical and quantitative modeling of ERK, PI3K/Akt,
and Wnt/?-catenin signaling crosstalk to show the dynamics of
signaling responses during genetic and epigenetic changes in
cancer. ERK, PI3K/Akt, and Wnt/?-catenin signaling crosstalk
networks include both intra and inter-pathway feedback loops
which function in a controlled fashion in a healthy cell. Our
results show that cancerous perturbations of components such as
EGFR, Ras, B-Raf, PTEN, and components of the destruction
complex cause extreme fragility in the network and
constitutively activate inter-pathway positive feedback loops.
We observed that the aberrant signaling response due to the
failure of specific network components is transmitted
throughout the network via crosstalk, generating an additive
effect on cancer growth and proliferation.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000648.
To cite BioModels Database, please use:
Chelliah V et al. BioModels: ten-year
anniversary. Nucl. Acids Res. 2015, 43(Database
issue):D542-8.
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.
2024-09-02 | BIOMD0000000648 | BioModels
Project description:PRDM15 safeguards naïve pluripotency by transcriptionally regulating WNT and MAPK/ERK signaling
| PRJNA297672 | ENA
Project description:Padala2017- ERK, PI3K/Akt and Wnt signalling
network (bRaf mutated)
Crosstalk model of the ERK, Wnt and Akt
signalling pathways with bRaf mutation
This model is described in the article:
Cancerous perturbations
within the ERK, PI3K/Akt, and Wnt/?-catenin signaling network
constitutively activate inter-pathway positive feedback
loops.
Padala RR, Karnawat R, Viswanathan
SB, Thakkar AV, Das AB.
Mol Biosyst 2017 May; 13(5):
830-840
Abstract:
Perturbations in molecular signaling pathways are a result
of genetic or epigenetic alterations, which may lead to
malignant transformation of cells. Despite cellular robustness,
specific genetic or epigenetic changes of any gene can trigger
a cascade of failures, which result in the malfunctioning of
cell signaling pathways and lead to cancer phenotypes. The
extent of cellular robustness has a link with the architecture
of the network such as feedback and feedforward loops.
Perturbation in components within feedback loops causes a
transition from a regulated to a persistently activated state
and results in uncontrolled cell growth. This work represents
the mathematical and quantitative modeling of ERK, PI3K/Akt,
and Wnt/?-catenin signaling crosstalk to show the dynamics of
signaling responses during genetic and epigenetic changes in
cancer. ERK, PI3K/Akt, and Wnt/?-catenin signaling crosstalk
networks include both intra and inter-pathway feedback loops
which function in a controlled fashion in a healthy cell. Our
results show that cancerous perturbations of components such as
EGFR, Ras, B-Raf, PTEN, and components of the destruction
complex cause extreme fragility in the network and
constitutively activate inter-pathway positive feedback loops.
We observed that the aberrant signaling response due to the
failure of specific network components is transmitted
throughout the network via crosstalk, generating an additive
effect on cancer growth and proliferation.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000653.
To cite BioModels Database, please use:
Chelliah V et al. BioModels: ten-year
anniversary. Nucl. Acids Res. 2015, 43(Database
issue):D542-8.
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.
2024-09-02 | BIOMD0000000653 | BioModels
Project description:Padala2017- ERK, PI3K/Akt and Wnt signalling
network (EGFR overexpression)
Crosstalk model of the ERK, Wnt and Akt
signalling pathways with EGFR overexpression.
This model is described in the article:
Cancerous perturbations
within the ERK, PI3K/Akt, and Wnt/?-catenin signaling network
constitutively activate inter-pathway positive feedback
loops.
Padala RR, Karnawat R, Viswanathan
SB, Thakkar AV, Das AB.
Mol Biosyst 2017 May; 13(5):
830-840
Abstract:
Perturbations in molecular signaling pathways are a result
of genetic or epigenetic alterations, which may lead to
malignant transformation of cells. Despite cellular robustness,
specific genetic or epigenetic changes of any gene can trigger
a cascade of failures, which result in the malfunctioning of
cell signaling pathways and lead to cancer phenotypes. The
extent of cellular robustness has a link with the architecture
of the network such as feedback and feedforward loops.
Perturbation in components within feedback loops causes a
transition from a regulated to a persistently activated state
and results in uncontrolled cell growth. This work represents
the mathematical and quantitative modeling of ERK, PI3K/Akt,
and Wnt/?-catenin signaling crosstalk to show the dynamics of
signaling responses during genetic and epigenetic changes in
cancer. ERK, PI3K/Akt, and Wnt/?-catenin signaling crosstalk
networks include both intra and inter-pathway feedback loops
which function in a controlled fashion in a healthy cell. Our
results show that cancerous perturbations of components such as
EGFR, Ras, B-Raf, PTEN, and components of the destruction
complex cause extreme fragility in the network and
constitutively activate inter-pathway positive feedback loops.
We observed that the aberrant signaling response due to the
failure of specific network components is transmitted
throughout the network via crosstalk, generating an additive
effect on cancer growth and proliferation.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000656.
To cite BioModels Database, please use:
Chelliah V et al. BioModels: ten-year
anniversary. Nucl. Acids Res. 2015, 43(Database
issue):D542-8.
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.
2024-09-02 | BIOMD0000000656 | BioModels