2010 Fiscal Year Final Research Report
TIRAP, an Adaptor Protein for TLR2/4, Transduces a signal from RAGE Phosphorylated upon Ligand Binding
| Project/Area Number |
21689011
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| Research Category |
Grant-in-Aid for Young Scientists (A)
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| Allocation Type | Single-year Grants |
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| Research Field |
Pathological medical chemistry
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| Research Institution | Okayama University |
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Principal Investigator |
SAKAGUCHI Masakiyo Okayama University, 大学院・医歯薬学総合研究科, 准教授 (70379840)
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| Project Period (FY) |
2009 – 2010
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| Keywords | シグナル伝達 / イメージング / 多機能受容体 / RAGE / S100タンパク質 |
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| Research 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 PKCz 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.
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