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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.
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Cancerous perturbations within the ERK, PI3K/Akt, and Wnt/β-catenin signaling network constitutively activate inter-pathway positive feedback loops.
- Rahul Rao Padala, Rishabh Karnawat, Satish Bharathwaj Viswanathan, Abhishek Vijay Thakkar, Asim Bikas Das
- Molecular bioSystems , 5/ 2017 , Volume 13 , Issue 5 , pages: 830-840 , PubMed ID: 28367561
- Department of Biotechnology, National Institute of Technology Warangal, Warangal, Telangana 506004, India. bikasasim@gmail.com asimbikas@nitw.ac.in.
- 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/β-catenin signaling crosstalk to show the dynamics of signaling responses during genetic and epigenetic changes in cancer. ERK, PI3K/Akt, and Wnt/β-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.
Submitter of this revision: Lucian Smith
Curator: Lucian Smith
Modellers: Emma Fairbanks, Rahuman S Malik-Sheriff
Metadata information
BioModels Database BIOMD0000000149
BioModels Database BIOMD0000000623
is (2 statements)
isDescribedBy (2 statements)
hasTaxon (1 statement)
hasProperty (5 statements)
Gene Ontology regulation of protein kinase B signaling
Gene Ontology regulation of canonical Wnt signaling pathway
Mathematical Modelling Ontology Ordinary differential equation model
Pathway Ontology cancer pathway
hasPart (4 statements)
KEGG Pathway MAPK signaling pathway
KEGG Pathway PI3K-Akt signaling pathway
KEGG Pathway Wnt signaling pathway
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