title: Chemoattractant concentration-dependent tuning of ERK signaling dynamics in migrating neutrophils.
abstract: The directed migration (chemotaxis) of neutrophils toward the bacterial peptide N-formyl-Met-Leu-Phe (fMLP) is a crucial process in immune defense against invading bacteria. While navigating through a gradient of increasing concentrations of fMLP, neutrophils and neutrophil-like HL-60 cells switch from exhibiting directional migration at low fMLP concentrations to exhibiting circuitous migration at high fMLP concentrations. The extracellular signal-regulated kinase (ERK) pathway is implicated in balancing this fMLP concentration-dependent switch in migration modes. We investigated the role and regulation of ERK signaling through single-cell analysis of neutrophil migration in response to different fMLP concentrations over time. We found that ERK exhibited gradated, rather than all-or-none, responses to fMLP concentration. Maximal ERK activation occurred in response to about 100 nM fMLP, and ERK inactivation was promoted by p38. Furthermore, we found that directional migration of neutrophils reached a maximal extent at about 100 nM fMLP and that ERK, but not p38, was required for neutrophil migration. Thus, our data suggest that, in chemotactic neutrophils responding to fMLP, ERK displays gradated activation and p38-dependent inhibition and that these ERK dynamics promote neutrophil migration.
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.|Green Center for Systems Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.|Green Center for Systems Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Liu
authors.affiliation: Green Center for Systems Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.|Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Lani F
authors.initials: LF
authors.lastname: Wu
authors.affiliation: Green Center for Systems Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.|Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Altschuler
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. melanie.cobb@utsouthwestern.edu.
authors.forename: Melanie H
authors.initials: MH
authors.lastname: Cobb
mesh_terms: D002465:Cell Movement / Q000187:drug effects* / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000276:immunology; D008297:Male; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology*; D009504:Neutrophils / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology*
chemical_list: D009240:N-Formylmethionine Leucyl-Phenylalanine; D048051:p38 Mitogen-Activated Protein Kinases