Etk/BMX, a Btk family tyrosine kinase, and Mal contribute to the cross-talk between MyD88 and FAK pathways.
MyD88 and focal adhesion kinase (FAK) are key adaptors involved in signaling downstream of TLR2, TLR4, and integrin alpha5beta1, linking pathogen-associated molecule detection to the initiation of proinflammatory response. The MyD88 and integrin pathways are interlinked, but the mechanism of this cross-talk is not yet understood. In this study we addressed the involvement of Etk, which belongs to the Tec family of tyrosine kinases, in the cross-talk between the integrin/FAK and the MyD88 pathways in fibroblast-like synoviocytes (FLS) and in IL-6 synthesis. Using small interfering RNA blockade, we report that Etk plays a major role in LPS- and protein I/II (a model activator of FAK)-dependent IL-6 release by activated FLS. Etk is associated with MyD88, FAK, and Mal as shown by coimmunoprecipitation. Interestingly, knockdown of Mal appreciably inhibited IL-6 synthesis in response to LPS and protein I/II. Our results also indicate that LPS and protein I/II induced phosphorylation of Etk and Mal in rheumatoid arthritis FLS via a FAK-dependent pathway. In conclusion, our data provide support that, in FLS, Etk and Mal are implicated in the cross-talk between FAK and MyD88 and that their being brought into play is clearly dependent on FAK.
Semaan
Noha
N
Laboratoire Physiopathologie des Arthrites, Université Louis Pasteur de Strasbourg, Unité de Formation et de Recherche Sciences Pharmaceutiques, Illkirch, France.
Alsaleh
Ghada
G
Gottenberg
Jacques-Eric
JE
Wachsmann
Dominique
D
Sibilia
Jean
J
D000077329:Agammaglobulinaemia Tyrosine Kinase; D001426:Bacterial Proteins / Q000502:physiology; D002450:Cell Communication / Q000276:immunology*; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D039482:Integrin alpha5 / Q000378:metabolism / Q000502:physiology; D019012:Integrin beta1 / Q000378:metabolism / Q000502:physiology; D008213:Lymphocyte Activation / Q000276:immunology; D026901:Membrane Transport Proteins / Q000378:metabolism / Q000502:physiology*; D005810:Multigene Family / Q000276:immunology; D009185:Myelin Proteins / Q000378:metabolism / Q000502:physiology*; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism / Q000502:physiology*; D011510:Proteolipids / Q000378:metabolism / Q000502:physiology*; D020239:Receptor Cross-Talk / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D013583:Synovial Membrane / Q000201:enzymology / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000378:metabolism / Q000502:physiology
D001426:Bacterial Proteins; D039482:Integrin alpha5; D019012:Integrin beta1; C569026:MAL protein, human; C507779:MYD88 protein, human; D026901:Membrane Transport Proteins; D009185:Myelin Proteins; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D053594:Myeloid Differentiation Factor 88; D011510:Proteolipids; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; C508943:protein I-II, Streptococcus mutans; C492367:BMX protein, human; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human