title: Altering the threshold of an excitable signal transduction network changes cell migratory modes.
abstract: The diverse migratory modes displayed by different cell types are generally believed to be idiosyncratic. Here we show that the migratory behaviour of Dictyostelium was switched from amoeboid to keratocyte-like and oscillatory modes by synthetically decreasing phosphatidylinositol-4,5-bisphosphate levels or increasing Ras/Rap-related activities. The perturbations at these key nodes of an excitable signal transduction network initiated a causal chain of events: the threshold for network activation was lowered, the speed and range of propagating waves of signal transduction activity increased, actin-driven cellular protrusions expanded and, consequently, the cell migratory mode transitions ensued. Conversely, innately keratocyte-like and oscillatory cells were promptly converted to amoeboid by inhibition of Ras effectors with restoration of directed migration. We use computational analysis to explain how thresholds control cell migration and discuss the architecture of the signal transduction network that gives rise to excitability.
authors.affiliation: Department of Biological Chemistry, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, USA.
authors.forename: Yuchuan
authors.identifier: 0000-0003-0600-6609
authors.initials: Y
authors.lastname: Miao
authors.affiliation: Department of Electrical and Computer Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, Maryland 21205, USA.
authors.forename: Sayak
authors.initials: S
authors.lastname: Bhattacharya
authors.affiliation: Department of Cell Biology and Center for Cell Dynamics, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Edwards
authors.affiliation: State Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Huaqing
authors.initials: H
authors.lastname: Cai
authors.affiliation: Department of Cell Biology and Center for Cell Dynamics, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, USA.
authors.forename: Takanari
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Department of Electrical and Computer Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, Maryland 21205, USA.|Department of Cell Biology and Center for Cell Dynamics, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, USA.
authors.forename: Pablo A
authors.identifier: 0000-0002-0840-155X
authors.initials: PA
authors.lastname: Iglesias
authors.affiliation: Department of Cell Biology and Center for Cell Dynamics, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, USA.
authors.forename: Peter N
authors.initials: PN
authors.lastname: Devreotes
mesh_terms: D000199:Actins / Q000378:metabolism; D015374:Biosensing Techniques; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D003198:Computer Simulation; D000242:Cyclic AMP / Q000494:pharmacology; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D004023:Dictyostelium / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D059008:Time-Lapse Imaging
chemical_list: D000199:Actins; D019269:Phosphatidylinositol 4,5-Diphosphate; D049452:Green Fluorescent Proteins; D000242:Cyclic AMP