Network-based identification of feedback modules that control RhoA activity and cell migration.

Abstract

Cancer cell migration enables metastatic spread causing most cancer deaths. Rho-family GTPases control cell migration, but being embedded in a highly interconnected feedback network, the control of their dynamical behavior during cell migration remains elusive. To address this question, we reconstructed the Rho-family GTPases signaling network involved in cell migration, and developed a Boolean network model to analyze the different states and emergent rewiring of the Rho-family GTPases signaling network at protrusions and during extracellular matrix-dependent cell migration. Extensive simulations and experimental validations revealed that the bursts of RhoA activity induced at protrusions by EGF are regulated by a negative-feedback module composed of Src, FAK, and CSK. Interestingly, perturbing this module interfered with cyclic Rho activation and extracellular matrix-dependent migration, suggesting that CSK inhibition can be a novel and effective intervention strategy for blocking extracellular matrix-dependent cancer cell migration, while Src inhibition might fail, depending on the genetic background of cells. Thus, this study provides new insights into the mechanisms that regulate the intricate activation states of Rho-family GTPases during extracellular matrix-dependent migration, revealing potential new targets for interfering with extracellular matrix-dependent cancer cell migration.

• Authors: Tae-Hwan Kim, Naser Monsefi, Je-Hoon Song, Alex von Kriegsheim, Drieke Vandamme, Olivier Pertz, Boris N Kholodenko, Walter Kolch, Kwang-Hyun Cho
• Journal: Journal of molecular cell biology (J Mol Cell Biol) Vol. 7 Issue 3 Pg. 242-52 (Jun 2015) ISSN: 1759-4685 [Electronic] United States
• PMID: 25780058 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author (2015). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. All rights reserved.

Chemical References

• RHOA protein, human
• rhoA GTP-Binding Protein

Topics

• Cell Movement
• Cluster Analysis
• Computer Simulation
• Epigenesis, Genetic
• Epithelial-Mesenchymal Transition
• Gene Expression Regulation, Neoplastic
• Gene Regulatory Networks
• Humans
• Models, Genetic
• Neoplasms (enzymology, genetics, pathology)
• Transcriptome
• rhoA GTP-Binding Protein (metabolism)