2005 Fiscal Year Final Research Report Summary
Study of the signaling network via mutifundtional receptor, RAGE.
| Project/Area Number |
16570113
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Functional biochemistry
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| Research Institution | KANAZAWA UNIVERSITY |
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Principal Investigator |
WATANABE Takuo Kanazawa University, Graduate School of Medical Science, Associate Professor, 医学系研究科, 助教授 (40303268)
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| Co-Investigator(Kenkyū-buntansha) |
YONEKURA Hideto Kanazawa University, Graduate School of Medical Science, Associate Professor, 医学系研究科, 助教授 (80240373)
YAMAMOTO Yasuhiko Kanazawa University, Graduate School of Medical Science, Instructor, 医学系研究科, 助手 (20313637)
YAMAMOTO Hiroshi Kanazawa University, Graduate School of Medical Science, Professor, 医学系研究科, 教授 (00115198)
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| Project Period (FY) |
2004 – 2005
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| Keywords | RAGE / AGE / signaling / tyrosine phosphorylation / co-receptor |
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| Research Abstract |
RAGE (receptor for advanced glycation endproducts) is a cell surface receptor that bind several ligands, such as AGE (advanced glycation endproducts), HMGB-1 (high molecular group box-1 protein), amyloid beta. The intracellular signals evoked by RAGE-ligand interaction were thought to play pivotal roles in development of various diseases. However, the mechanism of generation of intracellular signals by RAGE was poorly understood.
In this research we revealed the presence of novel signaling pathway that is activated by the association of RAGE (receptor for advanced glycation endproducts) with its ligands. The pathway appears to involve tyrosine phosphorylation. We also found tyrosine-phosphorylated proteins that associate with RAGE on cell surface.
(1) We found increased tyrosine-phosphorylation of several proteins after ligand stimulation. Their phosphorylation requires cytoplasmic domain of RAGE because the increase of tyrosine-phosphorylation was not observed in a cell line that expres
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s cytoplasmic domain-deleted RAGE. We identified several candidates of those proteins by mass-spectrometry.
(2) We revealed that the stimulation-dependent tyrosine phosphorylation event was located upstream of ERK activation or on ERK-independent signaling pathway, using kinase inhibitors. Furthermore, tyrosine phosphorylation of a few proteins was regulated by tyrosine phosphatase.
(3) We found that several tyrosine-phosphorylated proteins associated with RAGE on cell surface using cross-linking followed by immunoprecipitation.
(4) We found that the tyrosine phosphorylation of the RAGE associated proteins was enhanced by ligand stimulation in dose-dependent and time-dependent manner. These proteins might be co-receptors of RAGE.
(5) We identified a known whose tyrosine-phosphorylation was enhanced by RAGE ligands using antibody array that evaluate tyrosine phosphorylation of known receptor tyrosine. A few known receptor tyrosine kinases were constitutively activated by full-length RAGE or cytoplasmic domain-deleted RAGE. These receptors might be involved in RAGE dependent-signaling pathways Less
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