Cancerous perturbations within the ERK, PI3K/Akt, and Wnt/β-catenin signaling network constitutively activate inter-pathway positive feedback loops
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/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.
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The number of species in the surveyed models, without considering compounds or different attributes or states such as phosphorylation state, ranges from 2 (in [31]) to 30 (in [53]).
“The number of species without considering compounds or different attributes or states, such as the phosphorylation state, ranges from 2 (in [31]) to 30 (in [53]).”
From Relating simulation studies by provenance—Developing a family of Wnt signaling models (2021) · cites this paper as [53]
All other simulation studies either used wet-lab data from other publications or did not explicitly refer to wet-lab data at all [29, 30, 33, 34, 39, 41, 53].
“All other simulation studies either used wet-lab data from other publications or did not explicitly refer to wet-lab data at all [29, 30, 33, 34, 39, 41, 53].”
From Relating simulation studies by provenance—Developing a family of Wnt signaling models (2021) · cites this paper as [53]
Two out of 19 studies did not explicitly state assumptions ([29, 53]).
“Furthermore, two out of 19 studies did not explicitly state assumptions ([29, 53]).”
From Relating simulation studies by provenance—Developing a family of Wnt signaling models (2021) · cites this paper as [53]
Some authors just calibrated their simulation models ([33, 46, 48, 49, 53, 57]).
“Some authors just calibrated their simulation models ([33, 46, 48, 49, 53, 57])”
From Relating simulation studies by provenance—Developing a family of Wnt signaling models (2021) · cites this paper as [53]
A fourth cluster forms around studies that include MAPK/ERK [32] or MAPK/ERK + PI3K/Akt [53].
“A forth cluster forms around studies that include MAPK/ERK [32] or MAPK/ERK + PI3K/Akt [53].”
From Relating simulation studies by provenance—Developing a family of Wnt signaling models (2021) · cites this paper as [53]
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- Authors
- Padala, R. R., Karnawat, R., Viswanathan, S. B., Thakkar, A. V., & Das, A. B.
- Affiliations
- National Institute of Technology Warangal (IN)
- Corresponding author
- Das, Asim Bikas
- ORCID
- Venue
- Molecular BioSystems
- Publisher
- Oxford University Press (OUP)
- Published
- 2017-03-24
- Volume
- 13
- Issue
- 5
- Pages
- 830-840
- ISSN
- 1742-2051 (ISSN-L)
- 1742-206X
- OpenAlex
- W2597995360
- Cited by
- 33
- References
- 86
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 5 · 2023: 1 · 2022: 3 · 2021: 7 · 2020: 1 · 2019: 7 · 2018: 4 · 2017: 2
- FWCI
- 1.56
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular BioSystems (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Physical Sciences › Mathematics › Modeling and Simulation › Mathematical Biology Tumor Growth
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- ERK signaling, PI3K/Akt signaling, Wnt/β-catenin signaling, positive feedback loop, network fragility, cancer, EGFR, Ras, BRAF, PTEN, network dynamics, mathematical modeling of signaling
- MeSH terms
- Humans, Models, Theoretical, Neoplasms, Genetic Variation, Gene Expression Regulation, Neoplastic, Computational Biology, Phosphatidylinositol 3-Kinases, MAP Kinase Signaling System, Feedback, Physiological, Epigenesis, Genetic, Proto-Oncogene Proteins c-akt, Gene Regulatory Networks, Wnt Signaling Pathway
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