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Title: | A MAPK-Driven Feedback Loop Suppresses Rac Activity to Promote RhoA-Driven Cancer Cell Invasion |
Authors: | Hetmanski, JHR Zindy, E Schwartz, JM Caswell, PT |
Keywords: | small interfering RNA;cell migration;fluorescence resonance energy transfer;guanosine triphosphatase;cancer cell migration;actins;signaling networks;transfection |
Issue Date: | 1-May-2016 |
Publisher: | PLOS |
Citation: | Hetmanski, J.H.R. et al. (2016) 'A MAPK-Driven Feedback Loop Suppresses Rac Activity to Promote RhoA-Driven Cancer Cell Invasion', PLoS Computational Biology, 12 (5), e1004909, pp. 1 - 27. doi: 10.1371/journal.pcbi.1004909. |
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. |
Description: | Data Availability: All relevant data are within the paper and its Supporting Information files. Supporting Information is available online at: https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1004909#sec024 . |
URI: | https://bura.brunel.ac.uk/handle/2438/28529 |
DOI: | https://doi.org/10.1371/journal.pcbi.1004909 |
ISSN: | 1553-734X |
Other Identifiers: | ORCiD: Joseph H. R. Hetmanski https://orcid.org/0000-0002-1493-351X ORCiD: Jean-Marc Schwartz https://orcid.org/0000-0002-6472-0184 ORCiD: Patrick T. Caswell https://orcid.org/0000-0002-2633-2324 e1004909 |
Appears in Collections: | Dept of Life Sciences Research Papers |
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FullText.pdf | Copyright: © 2016 Hetmanski et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. | 6.34 MB | Adobe PDF | View/Open |
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