title: 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.affiliation: Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea.
authors.forename: Tae-Hwan
authors.initials: TH
authors.lastname: Kim
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Naser
authors.initials: N
authors.lastname: Monsefi
authors.affiliation: Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea.
authors.forename: Je-Hoon
authors.initials: JH
authors.lastname: Song
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Alex
authors.initials: A
authors.lastname: von Kriegsheim
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Drieke
authors.initials: D
authors.lastname: Vandamme
authors.affiliation: Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Pertz
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Boris N
authors.initials: BN
authors.lastname: Kholodenko
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland ckh@kaist.ac.kr walter.kolch@ucd.ie.
authors.forename: Walter
authors.initials: W
authors.lastname: Kolch
authors.affiliation: Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea ckh@kaist.ac.kr walter.kolch@ucd.ie.
authors.forename: Kwang-Hyun
authors.initials: KH
authors.lastname: Cho
mesh_terms: D002465:Cell Movement; D016000:Cluster Analysis; D003198:Computer Simulation; D044127:Epigenesis, Genetic; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D008957:Models, Genetic; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D059467:Transcriptome; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: C066737:RHOA protein, human; D020742:rhoA GTP-Binding Protein
keywords: Boolean network model; Rho-family GTPases; cell migration; cyclical RhoA bursts; signaling network