Year-end Sale % OFF 
Abstract
Oxidative modification of low-density lipoprotein (LDL) turns it into an endogenous ligand recognized by pattern-recognition receptors. We have demonstrated that minimally oxidized LDL (mmLDL) binds to CD14 and mediates TLR4/MD-2-dependent responses in macrophages, many of which are MyD88-independent. We have also demonstrated that the mmLDL activation leads to recruitment of spleen tyrosine kinase (Syk) to TLR4 and TLR4 and Syk phosphorylation. In this study, we produced a macrophage-specific Syk knockout mouse and used primary Syk−/− macrophages in our studies. We demonstrated that Syk mediated phosphorylation of ERK1/2 and JNK, which in turn phosphorylated c-Fos and c-Jun, respectively, as assessed by an in vitro kinase assay. c-Jun phosphorylation was also mediated by IKKε. c-Jun and c-Fos bound to consensus DNA sites and thereby completed an AP-1 transcriptional complex and induced expression of CXCL2 and IL-6. These results suggest that Syk plays a key role in TLR4-mediated macrophage responses to host-generated ligands, like mmLDL, with subsequent activation of an AP-1 transcription program.
Highlights
Spleen tyrosine kinase (Syk) is best known as a tyrosine kinase involved in signaling initiated by B cell receptor, T cell receptor or Fc receptor
We demonstrate that Syk regulates ERK1/2-dependent phosphorylation of c-Fos and JNK/IKKedependent phosphorylation of c-Jun, as well as c-Fos and c-Jun binding to DNA and AP-1-dependent expression of CXCL2 and IL6
Using minimally oxidized LDL (mmLDL) as an activator of toll-like receptor-4 (TLR4)-dependent responses in primary macrophages, in this study we demonstrated that Syk regulates ERK1/2-dependent phosphorylation of c-Fos and JNKand IKKe-dependent phosphorylation of c-Jun, leading to AP-1dependent expression of proinflammatory cytokines
Summary
Spleen tyrosine kinase (Syk) is best known as a tyrosine kinase involved in signaling initiated by B cell receptor, T cell receptor or Fc receptor. Ligand binding to these receptors leads to recruitment of signaling proteins with immunoreceptor tyrosine-based activation motifs (ITAMs). Ensuing phosphorylation of tandem tyrosines in an ITAM leads to the ITAM binding with Syk via Syk’s tandem SH2 domains, with subsequent Syk activation. In addition to the SH-2-mediated binding to ITAMs, Syk binds to b-integrins via a site distinct from the site of phospho-tyrosine binding [2,3] and coordinates integrin- and ITAMdependent signaling cascades
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
