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The proline-rich tyrosine kinase Pyk2 modulates integrin-mediated neutrophil adhesion and reactive oxygen species generation.
Canino, Jessica; Guidetti, Gianni Francesco; Galgano, Luca; Vismara, Mauro; Minetti, Giampaolo; Torti, Mauro; Canobbio, Ilaria.
Afiliación
  • Canino J; Department of Biology and Biotechnology, University of Pavia, Italy; Scuola Universitaria Superiore, IUSS, Pavia, Italy.
  • Guidetti GF; Department of Biology and Biotechnology, University of Pavia, Italy.
  • Galgano L; Department of Biology and Biotechnology, University of Pavia, Italy; Scuola Universitaria Superiore, IUSS, Pavia, Italy.
  • Vismara M; Department of Biology and Biotechnology, University of Pavia, Italy.
  • Minetti G; Department of Biology and Biotechnology, University of Pavia, Italy.
  • Torti M; Department of Biology and Biotechnology, University of Pavia, Italy.
  • Canobbio I; Department of Biology and Biotechnology, University of Pavia, Italy. Electronic address: ilaria.canobbio@unipv.it.
Biochim Biophys Acta Mol Cell Res ; 1867(10): 118799, 2020 10.
Article en En | MEDLINE | ID: mdl-32693110
ABSTRACT
Neutrophils are first responders in infection and inflammation. They are able to roll, adhere and transmigrate through the endothelium to reach the site of infection, where they fight pathogens through secretion of granule contents, production of reactive oxygen species, extrusion of neutrophil extracellular traps, and phagocytosis. In this study we explored the role of the non-receptor focal adhesion kinase Pyk2 in neutrophil adhesion and activation. Using a specific Pyk2 pharmacological inhibitor, PF-4594755, as well as Pyk2-deficient murine neutrophils, we found that Pyk2 is activated upon integrin αMß2-mediated neutrophil adhesion to fibrinogen. This process is triggered by Src family kinases-mediated phosphorylation and supported by Pyk2 autophosphorylation on Y402. In neutrophil adherent to fibrinogen, Pyk2 activates PI3K-dependent pathways promoting the phosphorylation of Akt and of its downstream effector GSK3. Pyk2 also dynamically regulates MAP kinases in fibrinogen-adherent neutrophils, as it stimulates p38MAPK but negatively regulates ERK1/2. Pharmacological inhibition of Pyk2 significantly prevented adhesion of human neutrophils to fibrinogen, and neutrophils from Pyk2-knockout mice showed a reduced ability to adhere compared to wildtype cells. Accordingly, neutrophil adhesion to fibrinogen was reduced upon inhibition of p38MAPK but potentiated by ERK1/2 inhibition. Neutrophil adherent to fibrinogen, but not to polylysine, were able to produce ROS upon lipopolysaccharide challenge and ROS production was completely suppressed upon inhibition of Pyk2. By contrast PMA-induced ROS production by neutrophil adherent to either fibrinogen or polylysine was independent from Pyk2. Altogether these results demonstrate that Pyk2 is an important effector in the coordinated puzzle regulating neutrophil adhesion and activation.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Antígeno de Macrófago-1 / Especies Reactivas de Oxígeno / Quinasa 2 de Adhesión Focal / Neutrófilos Límite: Animals / Humans Idioma: En Revista: Biochim Biophys Acta Mol Cell Res Año: 2020 Tipo del documento: Article País de afiliación: Italia

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Antígeno de Macrófago-1 / Especies Reactivas de Oxígeno / Quinasa 2 de Adhesión Focal / Neutrófilos Límite: Animals / Humans Idioma: En Revista: Biochim Biophys Acta Mol Cell Res Año: 2020 Tipo del documento: Article País de afiliación: Italia
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