ArticlePLoS computational biology2016
A MAPK-Driven Feedback Loop Suppresses Rac Activity to Promote RhoA-Driven Cancer Cell Invasion.
Article in PLoS computational biology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 38 citations in OpenAlex.
- Molecular Mechanisms of Thyroid Hormone Signaling in Thyroid Cancer: Oncogenesis, Progression, and Therapeutic Implications.Biomedicines · 2025Review
- Differential roles of cyclin-CDK1 complexes in cell migration and invasion.Journal of cell science · 2025Article
- In Silico Pleiotropy Analysis in KEGG Signaling Networks Using a Boolean Network Model.Biomolecules · 2022Article
- Revised model of the tissue factor pathway of thrombin generation: Role of the feedback activation of FXI.Journal of thrombosis and haemostasis : JTH · 2022Article
- Combinatorial mathematical modelling approaches to interrogate rear retraction dynamics in 3D cell migration.PLoS computational biology · 2021Article
- Navigating Multi-Scale Cancer Systems Biology Towards Model-Driven Clinical Oncology and Its Applications in Personalized Therapeutics.Frontiers in oncology · 2021Review
- Bridging from single to collective cell migration: A review of models and links to experiments.PLoS computational biology · 2020Review
- FHOD3 promotes carcinogenesis by regulating RhoA/ROCK1/LIMK1 signaling pathway in medulloblastoma.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2020Article
- Shedding new light on RhoA signalling as a drug targetSmall GTPases · 2020Article
- Tissue transglutaminase 2 regulates tumor cell tensional homeostasis by increasing contractility.Journal of cell science · 2020Article
- Membrane Tension Orchestrates Rear Retraction in Matrix-Directed Cell Migration.Developmental cell · 2019Article
- Uncoupling Traditional Functionalities of Metastasis: The Parting of Ways with Real-Time Assays.Journal of clinical medicine · 2019Review
- Control of adhesion and protrusion in cell migration by Rho GTPases.Current opinion in cell biology · 2019Review
- RMut: R package for a Boolean sensitivity analysis against various types of mutations.PloS one · 2019Article
- The extracellular matrix as a key regulator of intracellular signalling networks.British journal of pharmacology · 2019Review
- Casticin inhibits breast cancer cell migration and invasion by down-regulation of PI3K/Akt signaling pathway.Bioscience reports · 2018Article
- Vesicle trafficking pathways that direct cell migration in 3D matrices and in vivo.Traffic (Copenhagen, Denmark) · 2018Review
- Actin-Based Cell Protrusion in a 3D Matrix.Trends in cell biology · 2018Review
- Supervillin promotes epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma in hypoxia via activation of the RhoA/ROCK-ERK/p38 pathway.Journal of experimental & clinical cancer research : CR · 2018Article
- Rationalizing Rac1 and RhoA GTPase signaling: A mathematical approach.Small GTPases · 2018Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Cell migration in 3D microenvironments is fundamental to development, homeostasis and the pathobiology of diseases such as cancer. Rab-coupling protein (RCP) dependent co-trafficking of α5β1 and EGFR1 promotes cancer cell invasion into fibronectin (FN) containing extracellular matrix (ECM), by potentiating EGFR1 signalling at the front of invasive cells. This promotes a switch in RhoGTPase signalling to inhibit Rac1 and activate a RhoA-ROCK-Formin homology domain-containing 3 (FHOD3) pathway and generate filopodial actin-spike protrusions which drive invasion. To further understand the signalling network that drives RCP-driven invasive migration, we generated a Boolean logical model based on existing network pathways/models, where each node can be interrogated by computational simulation. The model predicted an unanticipated feedback loop, whereby Raf/MEK/ERK signalling maintains suppression of Rac1 by inhibiting the Rac-activating Sos1-Eps8-Abi1 complex, allowing RhoA activity to predominate in invasive protrusions. MEK inhibition was sufficient to promote lamellipodia formation and oppose filopodial actin-spike formation, and led to activation of Rac and inactivation of RhoA at the leading edge of cells moving in 3D matrix. Furthermore, MEK inhibition abrogated RCP/α5β1/EGFR1-driven invasive migration. However, upon knockdown of Eps8 (to suppress the Sos1-Abi1-Eps8 complex), MEK inhibition had no effect on RhoGTPase activity and did not oppose invasive migration, suggesting that MEK-ERK signalling suppresses the Rac-activating Sos1-Abi1-Eps8 complex to maintain RhoA activity and promote filopodial actin-spike formation and invasive migration. Our study highlights the predictive potential of mathematical modelling approaches, and demonstrates that a simple intervention (MEK-inhibition) could be of therapeutic benefit in preventing invasive migration and metastasis.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.