title: Src-family-tyrosine kinase Lyn is critical for TLR2-mediated NF-κB activation through the PI 3-kinase signaling pathway.
abstract: TLR2 has a prominent role in host defense against a wide variety of pathogens. Stimulation of TLR2 triggers MyD88-dependent signaling to induce NF-κB translocation, and activates a Rac1-PI 3-kinase dependent pathway that leads to transactivation of NF-κB through phosphorylation of the P65 NF-κB subunit. This transactivation pathway involves tyrosine phosphorylations. The role of the tyrosine kinases in TLR signaling is controversial, with discrepancies between studies using only chemical inhibitors and knockout mice. Here, we show the involvement of the tyrosine-kinase Lyn in TLR2-dependent activation of NF-κB in human cellular models, by using complementary inhibition strategies. Stimulation of TLR2 induces the formation of an activation cluster involving TLR2, CD14, PI 3-kinase and Lyn, and leads to the activation of AKT. Lyn-dependent phosphorylation of the p110 catalytic subunit of PI 3-kinase is essential to the control of PI 3-kinase biological activity upstream of AKT and thereby to the transactivation of NF-κB. Thus, Lyn kinase activity is crucial in TLR2-mediated activation of the innate immune response in human mononuclear cells.
authors.affiliation: Department of Infection, Immunity and Inflammation, Institut Cochin, Inserm, U1016, Paris, France Université Paris Descartes, Paris, France Department of Pediatrics, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Toubiana
authors.affiliation: Department of Infection, Immunity and Inflammation, Institut Cochin, Inserm, U1016, Paris, France Université Paris Descartes, Paris, France.
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Rossi
authors.affiliation: Department of Infection, Immunity and Inflammation, Institut Cochin, Inserm, U1016, Paris, France.
authors.forename: Nadia
authors.initials: N
authors.lastname: Belaidouni
authors.affiliation: Department of Infection, Immunity and Inflammation, Institut Cochin, Inserm, U1016, Paris, France Université Paris Descartes, Paris, France Medical Intensive Care Unit, Hôpital Cochin, AP-HP, Paris, France.
authors.forename: David
authors.initials: D
authors.lastname: Grimaldi
authors.affiliation: Department of Infection, Immunity and Inflammation, Institut Cochin, Inserm, U1016, Paris, France Université Paris Descartes, Paris, France Medical Intensive Care Unit, Hôpital Cochin, AP-HP, Paris, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Pene
authors.affiliation: Department of Infection, Immunity and Inflammation, Institut Cochin, Inserm, U1016, Paris, France Université Paris Descartes, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Chafey
authors.affiliation: Department of Infection, Immunity and Inflammation, Institut Cochin, Inserm, U1016, Paris, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Comba
authors.affiliation: Department of Infection, Immunity and Inflammation, Institut Cochin, Inserm, U1016, Paris, France Université Paris Descartes, Paris, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Camoin
authors.affiliation: Department of Infection, Immunity and Inflammation, Institut Cochin, Inserm, U1016, Paris, France Université Paris Descartes, Paris, France.
authors.forename: Georges
authors.initials: G
authors.lastname: Bismuth
authors.affiliation: Department of Infection, Immunity and Inflammation, Institut Cochin, Inserm, U1016, Paris, France Université Paris Descartes, Paris, France.
authors.forename: Yann-Erick
authors.initials: YE
authors.lastname: Claessens
authors.affiliation: Department of Infection, Immunity and Inflammation, Institut Cochin, Inserm, U1016, Paris, France Université Paris Descartes, Paris, France Medical Intensive Care Unit, Hôpital Cochin, AP-HP, Paris, France.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Mira
authors.affiliation: Department of Infection, Immunity and Inflammation, Institut Cochin, Inserm, U1016, Paris, France Université Paris Descartes, Paris, France Medical Intensive Care Unit, Hôpital Cochin, AP-HP, Paris, France jean-daniel.chiche@cch.aphp.fr.
authors.forename: Jean-Daniel
authors.initials: JD
authors.lastname: Chiche
mesh_terms: D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D015533:Transcriptional Activation; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D018950:Lipopolysaccharide Receptors; D046912:Multiprotein Complexes; D016328:NF-kappa B; D051195:Toll-Like Receptor 2; D019869:Phosphatidylinositol 3-Kinases; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases
keywords: Innate immunity; Lyn; PI 3-kinase; Toll-like receptor; signal transduction