@article{4a79fe7857f44ffb8c9eeed8add5dcbd,
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.",
author = "Yuchuan Miao and Sayak Bhattacharya and Marc Edwards and Huaqing Cai and Takanari Inoue and Iglesias, {Pablo A.} and Devreotes, {Peter N.}",
note = "Funding Information: The authors would like to thank C. Janetopoulos (University of the Sciences) for discussions on the roles of PtdIns(4,5)P2. We thank all members of the Devreotes, Iglesias and Inoue laboratories as well as members of the D. Robinson and M. Iijima laboratories (Johns Hopkins University) for helpful suggestions. We thank the R. Kay laboratory (MRC Laboratory of Molecular Biology, UK) for providing pikI− cells, and the M. Ueda laboratory (Osaka University, Japan) for Gγ-cells. We thank the DictyBase stock centre for providing rasC−/rasG− and amiB− cells. We thank the V. Bankaitis laboratory (Texas A&M Health Sciences Center) for providing constructs of nodulin. This work was supported by NIH grant R35 GM118177 (to P.N.D.), AFOSR MURI FA95501610052, DARPA HR0011-16-C-0139, and NIH Grant S10 OD016374 (to S. Kuo of the JHU Microscope Facility). Funding Information: The authors would like to thank C. Janetopoulos (University of the Sciences) for discussions on the roles of PtdIns(4, 5)P2. We thank all members of the Devreotes, Iglesias and Inoue laboratories as well as members of the D. Robinson and M. Iijima laboratories (Johns Hopkins University) for helpfulsuggestions. We thank the R. Kay laboratory (MRC Laboratory of Molecular Biology, UK) for providing pikI- cells, and the M. Ueda laboratory (Osaka University, Japan) for Gγ- cells. We thank the DictyBase stock centre for providing rasC-/rasG- and amiB- cells. We thank the V. Bankaitis laboratory (Texas A&M Health Sciences Center) for providing constructs of nodulin. This work was supported by NIH grant R35 GM118177 (to P.N.D.), AFOSR MURI FA95501610052, DARPA HR0011-16-C-0139, and NIH Grant S10 OD016374 (to S. Kuo of the JHU Microscope Facility). Publisher Copyright: {\textcopyright} 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.",
year = "2017",
doi = "10.1038/ncb3495",
language = "English (US)",
volume = "19",
pages = "329--340",
journal = "Nature cell biology",
issn = "1465-7392",
publisher = "Nature Publishing Group",
number = "4",
}