title: The directional response of chemotactic cells depends on a balance between cytoskeletal architecture and the external gradient.
abstract: Polarized migrating cells display signal transduction events, such as activation of phosphatidylinositol 3-kinase (PI3K) and Scar/Wave, and respond more readily to chemotactic stimuli at the leading edge. We sought to determine the basis of this polarized sensitivity. Inhibiting actin polymerization leads to uniform sensitivity. However, when human neutrophils were "stalled" by simultaneously blocking actin and myosin dynamics, they maintained the gradient of responsiveness to chemoattractant and also displayed noise-driven PIP3 flashes on the basal membrane, localized toward the front. Thus, polarized sensitivity does not require migration or cytoskeletal dynamics. The threshold for response is correlated with the static F-actin distribution, but not cell shape or volume changes, membrane fluidity, or the preexisting distribution of PI3K. The kinetics of responses to temporal and spatial stimuli were consistent with the local excitation global inhibition model, but the overall direction of the response was biased by the internal axis of polarity.
authors.affiliation: Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology and Pathophysiology, Fudan University Shanghai Medical College, Shanghai 200032, China.
authors.forename: Ming-Jie
authors.initials: MJ
authors.lastname: Wang
authors.affiliation: Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Artemenko
authors.affiliation: Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Basic Medicine, University of Shanghai for Science and Technology, Shanghai 200093, China.
authors.forename: Wen-Jie
authors.initials: WJ
authors.lastname: Cai
authors.affiliation: Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Electrical and Computer Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
authors.forename: Pablo A
authors.initials: PA
authors.lastname: Iglesias
authors.affiliation: Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: pnd@jhmi.edu.
authors.forename: Peter N
authors.initials: PN
authors.lastname: Devreotes
mesh_terms: D000199:Actins / Q000378:metabolism; D000577:Amides / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D016764:Cell Polarity / Q000187:drug effects*; D048430:Cell Shape / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D018914:Cells, Immobilized / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002630:Chemotactic Factors / Q000494:pharmacology*; D002633:Chemotaxis / Q000187:drug effects*; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism*; D047630:Depsipeptides / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D007700:Kinetics; D008560:Membrane Fluidity / Q000187:drug effects; D008856:Microscopy, Fluorescence; D009504:Neutrophils / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D053778:Thiazolidines / Q000494:pharmacology
chemical_list: D000199:Actins; D000577:Amides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002630:Chemotactic Factors; D047630:Depsipeptides; D011725:Pyridines; D053778:Thiazolidines; C057531:jasplakinolide; C108830:Y 27632; D051057:Proto-Oncogene Proteins c-akt; C037068:latrunculin B