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      An intracellular signaling hierarchy determines direction of migration in opposing chemotactic gradients

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          Abstract

          Neutrophils must follow both endogenous and bacterial chemoattractant signals out of the vasculature and through the interstitium to arrive at a site of infection. By necessity, in the setting of multiple chemoattractants, the neutrophils must prioritize, favoring end target chemoattractants (e.g., fMLP and C5a) emanating from the site of infection over intermediary endogenous chemoattractants (e.g., IL-8 and LTB 4) encountered en route to sites of infection. In this study, we propose a hierarchical model of two signaling pathways mediating the decision-making process of the neutrophils, which allows end target molecules to dominate over intermediary chemoattractants. In an under agarose assay, neutrophils predominantly migrated toward end target chemoattractants via p38 MAPK, whereas intermediary chemoattractant-induced migration was phosphoinositide 3-kinase (PI3K)/Akt dependent. When faced with competing gradients of end target and intermediary chemoattractants, Akt activation was significantly reduced within neutrophils, and the cells migrated preferentially toward end target chemoattractants even at 1/1,000th that of intermediary chemoattractants. End target molecules did not require chemotactic properties, since the p38 MAPK activator, LPS, also inhibited Akt and prevented migration to intermediary chemoattractants. p38 MAPK inhibitors not only reversed this hierarchy, such that neutrophils migrated preferentially toward intermediary chemoattractants, but also allowed neutrophils to be drawn out of a local end target chemoattractant environment and toward intermediary chemoattractants unexpectedly in an exaggerated (two- to fivefold) fashion. This was entirely related to significantly increased magnitude and duration of Akt activation. Finally, end target chemoattractant responses were predominantly Mac-1 dependent, whereas nondominant chemoattractants used primarily LFA-1. These data provide support for a two pathway signaling model wherein the end target chemoattractants activate p38 MAPK, which inhibits intermediary chemoattractant-induced PI3K/Akt pathway, establishing an intracellular signaling hierarchy.

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          Neuroscience. Developmental refining of neuroglial signaling?

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            Isolation of a major cell surface glycoprotein from fibroblasts.

            A cell surface component has been isolated in partially purified form from cultured chick embryo and chick heart fibroblasts. This glycoprotein is similar to a protein recently reported to be present at the surface of normal cells, and missing after neoplastic transformation. It is a major cell surface glycoprotein that is synthesized by cultured fibroblasts, but is not collagen. It is shown to be markedly trypsin-sensitive, and its recovery from the cell surface is dependent on cell density. It is excluded from Sephadex G-200, but is not rapidly sedimented by ultracentrifugation, and has an apparent molecular weight of 220,000. The isolation of this cell surface glycoprotein may now provide a means of determining its function.
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              Function of PI3Kgamma in thymocyte development, T cell activation, and neutrophil migration.

              Phosphoinositide 3-kinases (PI3Ks) regulate fundamental cellular responses such as proliferation, apoptosis, cell motility, and adhesion. Viable gene-targeted mice lacking the p110 catalytic subunit of PI3Kgamma were generated. We show that PI3Kgamma controls thymocyte survival and activation of mature T cells but has no role in the development or function of B cells. PI3Kgamma-deficient neutrophils exhibited severe defects in migration and respiratory burst in response to heterotrimeric GTP-binding protein (G protein)-coupled receptor (GPCR) agonists and chemotactic agents. PI3Kgamma links GPCR stimulation to the formation of phosphatidylinositol 3,4,5-triphosphate and the activation of protein kinase B, ribosomal protein S6 kinase, and extracellular signal-regulated kinases 1 and 2. Thus, PI3Kgamma regulates thymocyte development, T cell activation, neutrophil migration, and the oxidative burst.
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                Author and article information

                Journal
                J Cell Biol
                The Journal of Cell Biology
                The Rockefeller University Press
                0021-9525
                1540-8140
                14 October 2002
                : 159
                : 1
                : 91-102
                Affiliations
                Immunology Research Group, Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Alberta T2N 4N1, Canada
                Author notes

                Address correspondence to Paul Kubes, Immunology Research Group, University of Calgary, 3330 Hospital Dr. NW, Alberta T2N 4N1, Canada. Tel.: (403) 220-8558. Fax: (403) 283-1267. E-mail: pkubes@ 123456ucalgary.ca

                Article
                200202114
                10.1083/jcb.200202114
                2173486
                12370241
                415836d1-7fa8-442d-8e75-8cbd5ad53f93
                Copyright © 2002, The Rockefeller University Press
                History
                : 22 February 2002
                : 15 August 2002
                : 15 August 2002
                Categories
                Article

                Cell biology
                p38 mapk; pi3k gamma; chemotaxis; neutrophils; signal transduction
                Cell biology
                p38 mapk; pi3k gamma; chemotaxis; neutrophils; signal transduction

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