TIRAP, an adaptor protein for TLR2/4, transduces a signal from RAGE phosphorylated upon ligand binding

Masakiyo Sakaguchi, Hitoshi Murata, Ken-ichi Yamamoto, Tomoyuki Ono, Yoshihiko Sakaguchi, Akira Motoyama, Toshihiko Hibino, Ken Kataoka, Nam ho Huh

Research output: Contribution to journalArticle

109 Citations (Scopus)

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.

Original languageEnglish
Article numbere23132
JournalPLoS One
Volume6
Issue number8
DOIs
Publication statusPublished - 2011

Fingerprint

Toll-Like Receptor 2
Toll-Like Receptor 4
Ligands
receptors
Proteins
proteins
Cytoplasmic and Nuclear Receptors
Cellular Immunity
Advanced Glycosylation End Product-Specific Receptor
ligands
advanced glycation end products
Toll-like receptor 2
pathogenesis
inflammation
immune response
Inflammation
Molecules

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

TIRAP, an adaptor protein for TLR2/4, transduces a signal from RAGE phosphorylated upon ligand binding. / Sakaguchi, Masakiyo; Murata, Hitoshi; Yamamoto, Ken-ichi; Ono, Tomoyuki; Sakaguchi, Yoshihiko; Motoyama, Akira; Hibino, Toshihiko; Kataoka, Ken; Huh, Nam ho.

In: PLoS One, Vol. 6, No. 8, e23132, 2011.

Research output: Contribution to journalArticle

Sakaguchi, Masakiyo ; Murata, Hitoshi ; Yamamoto, Ken-ichi ; Ono, Tomoyuki ; Sakaguchi, Yoshihiko ; Motoyama, Akira ; Hibino, Toshihiko ; Kataoka, Ken ; Huh, Nam ho. / TIRAP, an adaptor protein for TLR2/4, transduces a signal from RAGE phosphorylated upon ligand binding. In: PLoS One. 2011 ; Vol. 6, No. 8.
@article{bee0f456c2cb4c5a95a6daa4f0a17df0,
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.",
author = "Masakiyo Sakaguchi and Hitoshi Murata and Ken-ichi Yamamoto and Tomoyuki Ono and Yoshihiko Sakaguchi and Akira Motoyama and Toshihiko Hibino and Ken Kataoka and Huh, {Nam ho}",
year = "2011",
doi = "10.1371/journal.pone.0023132",
language = "English",
volume = "6",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "8",

}

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 -