title: Toll-like receptor-mediated tyrosine phosphorylation of paxillin via MyD88-dependent and -independent pathways.
abstract: Toll-like receptor (TLR)-mediated recognition of pathogens represents one of the most important mechanisms of innate immunity. A proximal signaling event of TLR is the direct binding of an adaptor protein MyD88 to TLR and recruitment of the IL-1R-associated kinase (IRAK). In the present study, we examined the effect of several TLR ligands on protein tyrosine phosphorylation in rat macrophages. Macrophage-activating lipopeptide-2 kDa (MALP2) and lipoarabinomannan were used as activators of TLR2, while lipopolysaccharides (LPS) and lipoteichoic acid were used as TLR4 ligands. All these ligands induced tyrosine phosphorylation of proline-rich tyrosine kinase 2 (Pyk2) and its substrate paxillin, an integrin-associated focal adhesion adaptor protein, in the macrophages. PP2, an inhibitor of Src family tyrosine kinases, prevented the TLR-induced phosphorylation of paxillin and Pyk2 without affecting TLR-induced IRAK activation. MALP2 failed to induce paxillin phosphorylation in the macrophages from MyD88-knockout mice. In contrast, the effect of LPS weakened, but was still observed even in the MyD88-deficient cells. Thus, TLR regulate the function of paxillin in an Src family-dependent mechanism through both MyD88-dependent and MyD88-independent pathways.
authors.affiliation: Division of Molecular Medical Science, Graduate School of Biomedical Sciences, Hiroshima University, Minami-ku, Hiroshima 734-8551, Japan. khazeki@hiroshima-u.ac.jp
authors.forename: Kaoru
authors.initials: K
authors.lastname: Hazeki
authors.forename: Naoyo
authors.initials: N
authors.lastname: Masuda
authors.forename: Kenji
authors.initials: K
authors.lastname: Funami
authors.forename: Naoe
authors.initials: N
authors.lastname: Sukenobu
authors.forename: Misako
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takeda
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Seya
authors.forename: Osamu
authors.initials: O
authors.lastname: Hazeki
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000502:physiology*; D019556:COS Cells; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D029721:Drosophila Proteins; D051418:Focal Adhesion Kinase 2; D053592:Interleukin-1 Receptor-Associated Kinases; D055666:Lipopeptides; D008264:Macrophages / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000502:physiology*; D053594:Myeloid Differentiation Factor 88; D009842:Oligopeptides / Q000502:physiology; D051419:Paxillin; D010750:Phosphoproteins / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D011956:Receptors, Cell Surface / Q000502:physiology*; D011971:Receptors, Immunologic / Q000502:physiology*; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014443:Tyrosine / Q000378:metabolism*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000502:physiology
chemical_list: C412373:AG 1879; D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D003598:Cytoskeletal Proteins; D029721:Drosophila Proteins; D055666:Lipopeptides; D008562:Membrane Glycoproteins; C507781:Myd88 protein, rat; D053594:Myeloid Differentiation Factor 88; D009842:Oligopeptides; D051419:Paxillin; D010750:Phosphoproteins; C496063:Pxn protein, rat; D011743:Pyrimidines; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C495343:Tlr2 protein, rat; C495347:Tlr4 protein, rat; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014443:Tyrosine; C106335:macrophage stimulatory lipopeptide 2; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D051418:Focal Adhesion Kinase 2; C496054:Ptk2b protein, rat; D019061:src-Family Kinases; D053592:Interleukin-1 Receptor-Associated Kinases