title: TIRAP, an adaptor protein for TLR2/4, transduces a signal from RAGE phosphorylated upon ligand binding.
abstract: The receptor for advanced glycation end products (RAGE) is thought to be involved in the pathogenesis of a broad range of inflammatory, degenerative and hyperproliferative diseases. It binds to diverse ligands and activates multiple intracellular signaling pathways. Despite these pivotal functions, molecular events just downstream of ligand-activated RAGE have been surprisingly unknown. Here we show that the cytoplasmic domain of RAGE is phosphorylated at Ser391 by PKCζ upon binding of ligands. TIRAP and MyD88, which are known to be adaptor proteins for Toll-like receptor-2 and -4 (TLR2/4), bound to the phosphorylated RAGE and transduced a signal to downstream molecules. Blocking of the function of TIRAP and MyD88 largely abrogated intracellular signaling from ligand-activated RAGE. Our findings indicate that functional interaction between RAGE and TLRs coordinately regulates inflammation, immune response and other cellular functions.
authors.affiliation: Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Kita-ku, Okayama, Japan.
authors.forename: Masakiyo
authors.initials: M
authors.lastname: Sakaguchi
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Murata
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Ono
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Sakaguchi
authors.forename: Akira
authors.initials: A
authors.lastname: Motoyama
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Hibino
authors.forename: Ken
authors.initials: K
authors.lastname: Kataoka
authors.forename: Nam-ho
authors.initials: NH
authors.lastname: Huh
mesh_terms: D015152:Blotting, Northern; D015153:Blotting, Western; D002460:Cell Line; D018920:Coculture Techniques; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D008024:Ligands; D008562:Membrane Glycoproteins / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D011485:Protein Binding; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000737:chemistry / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000378:metabolism / Q000502:physiology*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D000099221:Protein Kinase C zeta
chemical_list: D008024:Ligands; D008562:Membrane Glycoproteins; D011493:Protein Kinase C; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D017472:Receptors, Interleukin-1; D012694:Serine; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D000099221:Protein Kinase C zeta; C434984:TIRAP protein, human; C495342:TLR2 protein, human; C495345:TLR4 protein, human