TIRAP, an Adaptor Protein for TLR2/4, Transduces a signal from RAGE Phosphorylated upon Ligand Binding

• Project/Area Number: 21689011
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Pathological medical chemistry
• Research Institution: Okayama University
• Principal Investigator: SAKAGUCHI Masakiyo Okayama University, 大学院・医歯薬学総合研究科, 准教授 (70379840)
• Project Period (FY): 2009 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥21,450,000 (Direct Cost: ¥16,500,000、Indirect Cost: ¥4,950,000); Fiscal Year 2010: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2009: ¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000)
• 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

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.

Research Products

• [Journal Article] A new cytosolic pathway from a Parkinson's disease-associated kinase, BRPK/PINK1 : activation of AKT via MTORC2. (2011)
  • Author(s): Murata H, Sakaguchi M, Jin Y, Sakaguchi Y, Futami JI, Yamada H, Kataoka K, Huh NH.
  • Journal Title: J Biol Chem. 286 Pages: 7182-7189
  • Peer Reviewed
• [Journal Article] Expression of REIC/Dkk-3 in normal and hyperproliferative epidermis. (2011)
  • Author(s): Du G, Kataoka K, Sakaguchi M, Abarzua F, Than SS, Sonegawa H, Makino T, Shimizu T, Huh NH.
  • Journal Title: Exp Dermatol. 20 Pages: 273-277
  • Peer Reviewed
• [Journal Article] Intraperitoneal administration of an adenovirus vector carrying REIC/Dkk-3 suppresses peritoneal dissemination of scirrhous gastric carcinoma. (2011)
  • Author(s): Than SS, Kataoka K, Sakaguchi M, Murata H, Abarzua F, Taketa C, Du G, Yashiro M, Yanagihara K, Nasu Y, Kumon H, Huh NH.
  • Journal Title: Oncol Rep. 25 Pages: 989-995
  • Peer Reviewed
• [Journal Article] A new cytosolic pathway from a Parkinson's disease-associated kinase, BRPK/PINK1 : activation of AKT via MTORC2. (2011)
  • Author(s): Murata H, Sakaguchi M, Jin Y, Sakaguchi Y, Futami JI, Yamada H, Kataoka K, Huh NH
  • Journal Title: J Biol Chem Volume: 286 Pages: 7182-7189
  • Peer Reviewed
• [Journal Article] S100A11, a dual growth regulator of epidermal keratinocytes (2011)
  • Author(s): Sakaguchi M, Huh NH
  • Journal Title: Amino Acids Volume: (in press)
  • Peer Reviewed
• [Journal Article] Markedly elevated serum levels of calcium-binding S100A8/A9 proteins in psoriatic arthritis are due to activated monocytes/macrophages (2011)
  • Author(s): Aochi S, Tsuji K, Sakaguchi M, Huh NH, Tsuda T, Yamanishi K, Komine M, Iwatsuki K
  • Journal Title: J Am Acad Dermatol Volume: 64 Pages: 879-887
  • Peer Reviewed
• [Journal Article] S100A11, a dual growth regulator of epidermal keratinocytes. (2010)
  • Author(s): Sakaguchi M, Huh NH.
  • Journal Title: Amino Acids. In Press
  • Peer Reviewed
• [Journal Article] Markedly elevated serum levels of calcium-binding S100A8/A9 proteins in psoriatic arthritis are due to activated monocytes/macrophages. (2010)
  • Author(s): Aochi S, Tsuji K, Sakaguchi M, Huh NH, Tsuda T, Yamanishi K, Komine M, Iwatsuki K.
  • Journal Title: J Am Acad Dermatol. In Press
  • Peer Reviewed
• [Journal Article] Internalization of REIC/Dkk-3 protein by induced pluripotent stem cell-derived embryoid bodies and extra-embryonic tissues. (2010)
  • Author(s): Kataoka K, Sakaguchi M, Peng li K, Taketa C, Yamamoto K, Dui G, Funahashi H, Murata H, Huh NH.
  • Journal Title: Int J Mol Med 26 Pages: 853-859
  • Peer Reviewed
• [Journal Article] Expression pattern of REIC/Dkk-3 in various cell types and the implications of the soluble form in prostatic acinar development. (2010)
  • Author(s): Zhangi K, Watanabe M, Kashiwakura Y, Aili S, Edamura K, Huang P, Yamaguchi K, Nasu Y, Kobayashi Y, Sakaguchi M, Ochiai K, Yamada H, Takei K, Ueki H, Huh NH, Li M, Kaku H, Na Y, Kumon H.
  • Journal Title: Int J Oncol 37 Pages: 1495-1501
  • Peer Reviewed
• [Journal Article] Transcriptional regulation of a brown adipocyte-specific gene, UCP1, by KLF11 and KLF15. (2010)
  • Author(s): Yamamoto K, Sakaguchi M, Medina RJ, Niida A, Sakaguchi Y, Miyazaki M, Kataoka K, Huh NH.
  • Journal Title: Biochem Biophys Res Commun. 400 Pages: 175-80
  • Peer Reviewed
• [Journal Article] Down-regulation of BiP/GRP78 sensitizes resistant prostate cancer cells to gene-therapeutic overexpression of REIC/Dkk3. (2010)
  • Author(s): Tanimoto R, Sakaguchi M, Abarzua F, Kataoka K, Kurose K, Murata H, Nasu Y, Kumon H, Huh NH.
  • Journal Title: Int J Cancer. 126 Pages: 1562-1569
  • NAID: 120004724432
  • Peer Reviewed
• [Journal Article] Internalization of REIC/Dkk-3 protein by induced pluripotent stem cell-derived embryoid bodies and extra-embryonic tissues (2010)
  • Author(s): Kataoka K, Sakaguchi M, Peng li K, Taketa C, Yamamoto K, Dui G, Funahashi H, Murata H, Huh NH
  • Journal Title: Int J Mol Med Volume: 26 Pages: 853-859
  • Peer Reviewed
• [Journal Article] Expression pattern of REIC/Dkk-3 in various cell types and the implications of the soluble form in prostatic acinar development (2010)
  • Author(s): Zhangi K, Watanabe M, Kashiwakura Y, Aili S, Edamura K, Huang P, Yamaguchi K, Nasu Y, Kobayashi Y, Sakaguchi M., Ochiai K, Yamada H, Takei K, Ueki H, Huh NH, Li M, Kaku H, Na Y, Kumon H
  • Journal Title: Int J Oncol Volume: 37 Pages: 1495-1501
  • Peer Reviewed
• [Journal Article] Transcriptional regulation of a brown adipocyte-specific gene, UCP1, by KLF11 and KLF15 (2010)
  • Author(s): Yamamoto K, Sakaguchi M, Medina RJ, Niida A, Sakaguchi Y, Miyazaki M, Kataoka K, Huh NH
  • Journal Title: Biochem Biophys Res Commun Volume: 400 Pages: 175-180
  • Peer Reviewed
• [Journal Article] Down-regulation of BiP/GRP78 sensitizes resistant prostate cancer cells to gene-therapeutic overexpression of REIC/Dkk3 (2010)
  • Author(s): Tanimoto R, Sakaguchi M., Abarzua F, Kataoka K, Kurose K, Murata H, Nasu Y, Kumon H, Huh NH
  • Journal Title: Int J Cancer Volume: 126 Pages: 1562-1569
  • NAID: 120004724432
  • Peer Reviewed
• [Journal Article] Down-regulation of BiP/GRP78 sensitizes resistant prostate cancer cells to gene-therapeutic overexpression of REIC/Dkk3 (2010)
  • Author(s): Tanimoto R, Sakaguchi M, Abarzua F, Kataoka K, Kurose K, Murata H, Nasu Y, Kumon H, Huh NH
  • Journal Title: Int J Cancer 126 Pages: 15621569-15621569
  • NAID: 120004724432
  • Peer Reviewed
• [Journal Article] REIC/Dkk-3 overexpression downregulates P-glycoprotein in multidrug-resistant MCF7/ADR cells and induces apoptosis in breast cancer (2009)
  • Author(s): Kawasaki K, Watanabe M, Sakaguchi M, Ogasawara Y, Ochiai K, Nasu Y, Doihara H, Kashiwakura Y, Huh NH, Kumon H, Date H
  • Journal Title: Cancer Gene Ther 16 Pages: 6572-6572
  • Peer Reviewed
• [Journal Article] Immunological aspects of REIC/Dkk-3 in monocyte differentiation and tumor regression (2009)
  • Author(s): Watanabe M, Kashiwakura Y, Huang P, Ochiai K, Futami J, Li SA, Takaoka M, Nasu Y, Sakaguchi M, Huh NH, Kumon H
  • Journal Title: Int J Oncol 34 Pages: 657663-657663
  • Peer Reviewed
• [Journal Article] Overexpression of REIC/Dkk-3 in normal fibroblasts suppresses tumor growth via induction of IL-7 (2009)
  • Author(s): Sakaguchi M, Kataoka K, Abarzua F, Tanimoto R, Watanabe M, Murata H, Than SS, Kurose K, Kashiwakura Y, Ochiai K, Nasu Y, Kumon H, Huh NH
  • Journal Title: J Biol Chem 284 Pages: 1423614244-1423614244
  • Peer Reviewed
• [Journal Article] Suppression of carbon tetrachloride-induced liver fibrosis by transplantation of a clonal mesenchymal stem cell line derived from rat hone marrow (2009)
  • Author(s): Hardjo M, Miyazaki M, Sakaguchi M, Masaka T, Ibrahim S, Kataoka K, Huh NH
  • Journal Title: Cell Transplant 18 Pages: 8999-8999
  • Peer Reviewed
• [Journal Article] REIC/Dkk-3 stable transfection reduces the malignant phenotype of mouse prostate cancer RM9 cells (2009)
  • Author(s): Chen J, Watanabe M, Huang P, Sakaguchi M, Ochiai K, Nasu Y, Ouchida M, Huh NH, Shimizu K, Kashiwakura Y, Kaku H, Kumon H
  • Journal Title: Int J Mol Med 24 Pages: 789794-789794
  • Peer Reviewed
• [Presentation] TIRAP, an adaptor protein for TLR-2/-4, transduces a signal from RAGE phosphorylated upon ligand binding. (2010)
  • Author(s): Masakiyo Sakaguchi, Hitoshi Murata, Ken-ichi Yamamoto, Tomoyuki Ono, Yoshihiko Sakaguchi, Akira Motoyama, Toshihiko Hibino, Ken Kataoka, Nam-ho Huh.
  • Organizer: 第33回日本分子生物学会
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-07
• [Presentation] TIRAP, an adaptor protein for TLR-2/-4, transduces a signal from RAGE phosphorylated upon ligand binding (2010)
  • Author(s): Masakiyo Sakaguchi, Hitoshi Murata, Kenichi Yamamoto, Tomoyuki Ono, Yoshihiko Sakaguchi, Akira Motoyama, Toshihiko Hibino, Ken Kataoka, Nam-ho Huh
  • Organizer: 第33回日本分子生物学会
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-07
• [Presentation] Normal human fibroblasts mis-targetedly infected with adenovirus REIC have a tumor-suppressive ability in vivo (2009)
  • Author(s): 阪口政清、片岡健、フェルナンドアバルスア、谷本竜太、渡邉昌美、村田等、スエスエタン、那須保友、公文裕巳、許南
  • Organizer: 第32回日本分子生物学会
  • Place of Presentation: 横浜
  • Year and Date: 2009-12-12
• [Presentation] Promoter-based improvement of gene expression in cancer therapeutic adenovirus vector carrying REIC/Dkk-3 (2009)
  • Author(s): 阪口政清、片岡健、村田等、許南浩
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2009-10-03
• [Remarks] 阪口政清岡山大学若手トップリサーチャー研究奨励賞を受賞した。(2010年1月20日)
• [Patent(Industrial Property Rights)] 遺伝子発現を上昇させるシステム及び該システムを保持したベクター (2009)
  • Inventor(s): 阪口政清、公文裕巳、許南浩、渡部昌実
  • Industrial Property Rights Holder: 桃太郎源社
  • Industrial Property Number: 2009-264299
  • Filing Date: 2009-11-19
• [Patent(Industrial Property Rights)] 遺伝子発現を上昇させるシステム及び該システムを保持したベクター (2009)
  • Inventor(s): 阪口政清、公文裕巳、許南浩、渡邉昌美
  • Industrial Property Rights Holder: 岡山大学
  • Industrial Property Number: 2009-264299
  • Filing Date: 2009-11-19