TY - JOUR
T1 - TIRAP, an adaptor protein for TLR2/4, transduces a signal from RAGE phosphorylated upon ligand binding
AU - Sakaguchi, Masakiyo
AU - Murata, Hitoshi
AU - Yamamoto, Ken ichi
AU - Ono, Tomoyuki
AU - Sakaguchi, Yoshihiko
AU - Motoyama, Akira
AU - Hibino, Toshihiko
AU - Kataoka, Ken
AU - Huh, Nam ho
PY - 2011
Y1 - 2011
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=79960959115&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79960959115&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0023132
DO - 10.1371/journal.pone.0023132
M3 - Article
C2 - 21829704
AN - SCOPUS:79960959115
VL - 6
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 8
M1 - e23132
ER -