title: Bistability in the Rac1, PAK, and RhoA Signaling Network Drives Actin Cytoskeleton Dynamics and Cell Motility Switches.
abstract: Dynamic interactions between RhoA and Rac1, members of the Rho small GTPase family, play a vital role in the control of cell migration. Using predictive mathematical modeling, mass spectrometry-based quantitation of network components, and experimental validation in MDA-MB-231 mesenchymal breast cancer cells, we show that a network containing Rac1, RhoA, and PAK family kinases can produce bistable, switch-like responses to a graded PAK inhibition. Using a small chemical inhibitor of PAK, we demonstrate that cellular RhoA and Rac1 activation levels respond in a history-dependent, bistable manner to PAK inhibition. Consequently, we show that downstream signaling, actin dynamics, and cell migration also behave in a bistable fashion, displaying switches and hysteresis in response to PAK inhibition. Our results demonstrate that PAK is a critical component in the Rac1-RhoA inhibitory crosstalk that governs bistable GTPase activity, cell morphology, and cell migration switches.
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Kate M
authors.initials: KM
authors.lastname: Byrne
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Naser
authors.initials: N
authors.lastname: Monsefi
authors.affiliation: Edinburgh Cancer Research Centre, IGMM, University of Edinburgh, Edinburgh EH4 2XR, UK.
authors.forename: John C
authors.initials: JC
authors.lastname: Dawson
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Degasperi
authors.affiliation: Edinburgh Cancer Research Centre, IGMM, University of Edinburgh, Edinburgh EH4 2XR, UK.
authors.forename: Jimi-Carlo
authors.initials: JC
authors.lastname: Bukowski-Wills
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Natalia
authors.initials: N
authors.lastname: Volinsky
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Dobrzyński
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Marc R
authors.initials: MR
authors.lastname: Birtwistle
authors.affiliation: Institute of Theoretical and Experimental Biophysics, 142290 Pushchino, Moscow Region, Russia.
authors.forename: Mikhail A
authors.initials: MA
authors.lastname: Tsyganov
authors.affiliation: University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Anatoly
authors.initials: A
authors.lastname: Kiyatkin
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kida
authors.affiliation: Edinburgh Cancer Research Centre, IGMM, University of Edinburgh, Edinburgh EH4 2XR, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Finch
authors.affiliation: Edinburgh Cancer Research Centre, IGMM, University of Edinburgh, Edinburgh EH4 2XR, UK.
authors.forename: Neil O
authors.initials: NO
authors.lastname: Carragher
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland; Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland; School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Walter
authors.initials: W
authors.lastname: Kolch
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland; Co-senior author; Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia. Electronic address: lan.k.nguyen@monash.edu.
authors.forename: Lan K
authors.initials: LK
authors.lastname: Nguyen
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland; Edinburgh Cancer Research Centre, IGMM, University of Edinburgh, Edinburgh EH4 2XR, UK; Co-senior author; School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland. Electronic address: alex.vonkriegsheim@igmm.ed.ac.uk.
authors.forename: Alex
authors.initials: A
authors.lastname: von Kriegsheim
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland; Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland; School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland; Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia.
authors.forename: Boris N
authors.initials: BN
authors.lastname: Kholodenko
mesh_terms: D008841:Actin Cytoskeleton; D000199:Actins; D045744:Cell Line, Tumor; D002465:Cell Movement; D003599:Cytoskeleton; D006801:Humans; D017346:Protein Serine-Threonine Kinases; D015398:Signal Transduction; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein
chemical_list: D000199:Actins; D017346:Protein Serine-Threonine Kinases; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein
keywords: PAK inhibition; Rac1; RhoA; bistable switches; cell motility; mathematical modeling