The three-way switch operation of Rac1/RhoA GTPase-based circuit controlling amoeboid-hybrid-mesenchymal transition
Open accessAbstract
Metastatic carcinoma cells exhibit at least two different phenotypes of motility and invasion - amoeboid and mesenchymal. This plasticity poses a major clinical challenge for treating metastasis, while its underlying mechanisms remain enigmatic. Transitions between these phenotypes are mediated by the Rac1/RhoA circuit that responds to external signals such as HGF/SF via c-MET pathway. Using detailed modeling of GTPase-based regulation to study the Rac1/RhoA circuit's dynamics, we found that it can operate as a three-way switch. We propose to associate the circuit's three possible states to the amoeboid, mesenchymal and amoeboid/mesenchymal hybrid phenotype. In particular, we investigated the range of existence of and the transition between, the three states (phenotypes) in response to Grb2 and Gab1 - two downstream adaptors of c-MET. The results help to explain the regulation of metastatic cells by c-MET pathway and hence can contribute to the assessment of possible clinical interventions.
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The Hill function fits stimulus-response data in a wide set of biological systems.
“This agrees with general evidence that the Hill function fits stimulus-response data in a wide set of biological systems [123–128].”
From Fibromyalgia pathogenesis explained by a neuroendocrine multistable model (2024) · cites this paper as [123]
The Effective Model of the Small GTPase-based Regulatory Circuit section says the Hill function represents transcriptional self-activation of RhoA. It does not say that Hill functions fit stimulus-response data, let alone across a wide set of biological systems; searches for those claims found no supporting passage. Page numbers were not available in our copy. (LLM, conf=0.76)
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- Authors
- Huang, B., Lu, M., Jolly, M. K., Tsarfaty, I., Onuchic, J., & Ben-Jacob, E.
- Affiliations
- Center for Theoretical Biological Physics (US)
- Tel Aviv University (IL)
- Corresponding author
- Tsarfaty, Ilan
- Onuchic, José
- Venue
- Scientific Reports
- Published
- 2014-09-23
- Volume
- 4
- Issue
- 1
- Pages
- 6449-6449
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC4171704
- OpenAlex
- W2012938917
- Cited by
- 91
- References
- 60
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 5 · 2023: 10 · 2022: 7 · 2021: 7 · 2020: 12 · 2019: 5 · 2018: 5 · 2017: 12 · 2016: 8 · 2015: 12 · 2014: 1
- FWCI
- 4.51
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Rice Research Repository (Rice University) (submittedVersion)
- Funders
- National Science Foundation (1214457, 1427654)
- Cancer Prevention and Research Institute of Texas
- United States-Israel Binational Science Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- hybrid phenotype, metastatic carcinoma, C-MET signaling, hepatocyte growth factor, Grb2, Gab1, cell motility and invasion
- MeSH terms
- Amoeba, Cell Movement, Humans, Mesoderm, Neoplasm Metastasis, Neoplasms, rhoA GTP-Binding Protein, rac1 GTP-Binding Protein, Cell Shape, Epithelial-Mesenchymal Transition
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