サイトカインのシグナル制御機構とその破綻

• Project/Area Number: 13GS0011
• Research Category: Grant-in-Aid for Creative Scientific Research
• Allocation Type: Single-year Grants
• Research Institution: Kyushu University
• Principal Investigator: 吉村 昭彦 九州大学, 生体防御医学研究所, 教授 (90182815)
• Co-Investigator(Kenkyū-buntansha): 箕口 滋 九州大学, 生体防御医学研究所, 助手 (60322757) ; 岸原 健二 九州大学, 生体防御医学研究所, 助手 (80214774) ; 松崎 吾郎 琉球大学, 遺伝子実験センター, 教授 (30229455)
• Project Period (FY): 2001 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥339,950,000 (Direct Cost: ¥281,000,000、Indirect Cost: ¥58,950,000); Fiscal Year 2005: ¥81,250,000 (Direct Cost: ¥62,500,000、Indirect Cost: ¥18,750,000); Fiscal Year 2004: ¥85,800,000 (Direct Cost: ¥66,000,000、Indirect Cost: ¥19,800,000); Fiscal Year 2003: ¥88,400,000 (Direct Cost: ¥68,000,000、Indirect Cost: ¥20,400,000); Fiscal Year 2002: ¥84,500,000 (Direct Cost: ¥84,500,000)
• Keywords: チロシンキナ一ゼ / Ras / MAPキナーゼ / 消化管神経 / チロシンりん酸化 / サイトカイン / 好酸球 / 脂質ラフト / チロシンキナーゼ / STAT / SOCS / 炎症 / 造血因子 / キナーゼ抑制因子 / 関節炎リウマチ / 大腸炎 / 炎症性疾患 / JAK / 関節リウマチ / アデノウイルス / コクサッキーウイルス

Research Abstract

Spred/Sproutyファミリー分子はRas/Rafに結合して、ERK/MAP kinase経路を抑制する調節因子である。Spredは哺乳類では3種類報告されており、我々はSpred1,Spred2それぞれのノックアウト(KO)マウスを作製し、解析を行ってきた。Spred1はマスト細胞や好酸球などの末梢血液細胞の増殖を、Spred2は胎児期の血球発生を負に制御することを示した。我々はSprouty2やSprouty4がVEGFのシグナルを抑制する可能性について生化学的に検討した。その結果、Sprouty4はEGFによるERKの活性化には全く影響しなかったが、VEGFによるRafおよびERKの活性化はSprouty4により完全に抑制されることを示した。Sprouty4は活性化型PKCδによるRafの活性化も完全に抑制した。またSprouty4はC末端のRaf結合モチーフを介してRafを直接相互作用することも明らかにした。これらの結果から我々はSprouty4はVEGFRのシグナルのうちPLCγ-PKCδ-Raf経路をC末端の領域を介して抑制するという説を提唱した。さらにSprouty2-KOマウスを用いた解析からSprouty2はGDNFシグナルを負に制御し消化管神経の生存や神経ネットワーク形成を統御する重要な分子であることを示した。ショウジョウバエの表現型とあわせて考察すればSproutyは気管系や神経系などネットワーク構造の正確なリモデリングに重要な役割を担っていると思われる。Spredはもともと造血組織に多く発現し、Spred-1,Spred-2それぞれの単独KOマウスも好酸球、マスト細胞、赤血球などの産生充進が認められた。Spred1/Spred-2のDKOマウスはリンパ管の過形成によりE12〜14に死亡する。SpredはVEGF-Cのシグナルをリンパ管内皮細胞内で制御するのか、あるいは血球細胞と血管/リンパ管前駆細胞との相互作用を調節するか、いずれかの作用があるものと考えられる。

Research Products

• [Journal Article] Suppressor of Cytokine Signaling-1 Regulates Inflammatory Bowel Disease in Which Both IFNgamma and IL-4 Are Involved. (2006)
  • Author(s): Chinen T, kobatashi T, Ogata H, Yoshimura A, et al.
  • Journal Title: Gastroenterology. 130(2) Pages: 373-88
• [Journal Article] FLN29, a novel interferon-and LPS-inducible gene acting as a negative regulator of toll-like receptor signaling. (2005)
  • Author(s): MashimaR, Saeki K, Aki D, Yoshimura A, et al.
  • Journal Title: J Biol Chem. 280(5) Pages: 41289-97
• [Journal Article] The Sprouty-related protein,Spred-1,localizes in a lipid raft/caveola and inhibits ERK activation in collaboration with caveolin-1. (2005)
  • Author(s): Nonami A, Takemoto T, Kimura A, Yoshimura A, et al.
  • Journal Title: Genes Cells. 10(9) Pages: 887-95
• [Journal Article] The neuropeptide neuromedin U promotes inflammation by direct activation of mast cells. (2005)
  • Author(s): Moriyama M, Sato T, Inoue H, Yosyimura A, et al.
  • Journal Title: J Exp Med. 202(2) Pages: 217-24
• [Journal Article] Loss of mammalian Sprouty2 leads to enteric neuronal hyperplasia and esophageal achalasia. (2005)
  • Author(s): Taketomi T, Yoshiga D, Taniguchi K, Yoshimura A, et al.
  • Journal Title: Net Neurosci. 8(7) Pages: 855-7
• [Journal Article] Spred-1 negatively regulates allergen-induced airway eosinophilia and hyperresponsiveness. (2005)
  • Author(s): Inoue H, Kato R, Fukuyama S, Nonami A, Yoshimura A, et al.
  • Journal Title: J Exp Med. 20(1) Pages: 73-82
• [Journal Article] Spred-1 negatively regulates allergen-induced airway eosinophilia and hyperresponsiveness. (2005)
  • Author(s): Inoue H, Kato R, Fukuyama S, Nonami A, Yoshimura A
  • Journal Title: J Exp Med. 201 Pages: 73-82
• [Journal Article] SOCS1 is a suppressor of liver fibrosis and hepatitis-induced carcinogenesis (2004)
  • Author(s): Yoshida T, Ogata H, Kamio M, Joo A, Shiraishi H, Yoshimura A
  • Journal Title: J Exp Med 199 Pages: 1701-1707
• [Journal Article] Spred-2 Suppresses Aorta-Gonad-Mesonephros Hematopoiesis by Inhibiting MAP Kinase Activation. (2004)
  • Author(s): Nobuhisa I, Kato R, Inoue H, Takizawa M, Yoshimura A.
  • Journal Title: J Exp Med. 199 Pages: 737-742
• [Journal Article] Spred-1 negatively regulates interleukin-3-mediated ERK/mitogen-activated protein (MAP) kinase activation in hematopoietic cells. (2004)
  • Author(s): Nonami A, Kato R, Taniguchi K, Yoshiga S, Yoshimura A
  • Journal Title: J Biol Chem. 279 Pages: 52543-52551
• [Journal Article] SOCS1 inhibits HPV-E7-mediated transformation by inducing degradation of E7 protein. (2004)
  • Author(s): Kamio M, Yoshida T, Ogata H, Douchi T, Nagata Y, Yoshimura A.
  • Journal Title: Oncogene 17 Pages: 3108-3116
• [Journal Article] SOCS3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity (2004)
  • Author(s): Mori H, Hanada R, Hanada T, Aki D, Mashima R, Yoshimura A
  • Journal Title: Nature Mediciene 10 Pages: 739-743
• [Publications] Hamano S, Himeno K, Yoshimura A, et al.: "WSX-1 is required for resistance to Trypanosoma cruzi infection by regulation of proinflammatory cytokine production."Immunity. 19. 657-667 (2003)
• [Publications] Hanada T, Yoshida H, Yoshimura A, et al.: "Suppressor of cytokine signaling-1 is essential for suppressing dendritic cell activation and systemic autoimmunity."Immunity. 19. 437-450 (2003)
• [Publications] Seki Y, Inoue H, Nagata N, Yoshimura A, et al.: "SOCS-3 regulates onset and maintenance of TH2-mediated allergic responses Nature Medicine"Nature Medicine. 9. 1047-1054 (2003)
• [Publications] Yasukawa H, Ohishi M, Mori H, Yoshimura A, et al.: "IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages"Nature Immunol.. 4. 551-556 (2003)
• [Publications] Saeki K, Miura Y, Aki D, Yoshimura A, et al.: "The B cell-specific major raft protein, Raftlin is necessary for the integrity of lipid raft and BCR signal transduction."EMBO J. 22. 3015-3026 (2003)
• [Publications] Sasaki, A, Taketomi T, Kato R, Yoshimura A, et al.: "Mammalian Sprouty4 suppresses Ras-independent ERK activation by binding to Raf1."Nature Cell Biol. 5. 427-432 (2003)
• [Publications] Minoguchi M, Minoguchi S, Yoshimura A, et al.: "STAP-2/BKS, an adaptor/docking protein, modulates STAT3 activation in acute-phase response through its YXXQ motif"J Biol Chem. Jan 22(epub ahead of Print). (2003)
• [Publications] Sasaki A, Inagaki-Ohara K, Yoshimura A, et al.: "The N-terminal truncated isoform of SOCS3 translated from an alternative initiation AUG codon under stress conditions is stable due to the lack of a major ubiquitination site, Lys-6"J Biol Chem. 278. 2432-2436 (2003)
• [Publications] Yamada S, Shiono S, Joo A, Yoshimura A, et al.: "Control mechanism of JAK/STAT signal transduction pathway"FEBS Lett. 534. 190-196 (2003)
• [Publications] Kinjyo I, Hanada T, Yoshimura A, et al.: "SOCS1/JAB Is a Negative Regulator of LPS-Induced Macrophage Activation"Immunity. 17. 583-591 (2002)
• [Publications] Seki YI, Hayashi K, Yoshimura A, et al.: "Expression of the suppressor of cytokine signaling-5 (SOCS5) negatively regulates IL-4-dependent STAT6 activation and Th2 differentiation"Proc Natl Acad Sci. USA.. 99. 13003-13008 (2002)
• [Publications] Yoshida T, Hanada T, Yoshimura A, et al.: "Activation of STAT3 by the Hepatitis C virus core protein leads to cellular transformation"J. Exp. Med. 196. 641-653 (2002)
• [Publications] Wakioka T, Sasaki A, Yoshimura A, et al.: "Spred is Sprouty-related suppressor of Ras signaling"Nature. 412. 647-651 (2001)
• [Publications] Shouda T, Yoshida Yoshimura A, et al.: "Induction of the cytokine signal regulator SOCS3/CIS3 as a therapeutic strategv for treating inflammatory arthritis"J.Clin.Invest.. 108. 1781-1788 (2001)
• [Publications] Hanada T, Yoshida T, Kinjyo I, et al.: "A mutant from of JAB/SOOS1 augments the cytokine-induced JAK/STAT pathway by accelerating degration of willd-type JAB/CIS family proteins through the SOCS-"J.Biol.Chem.. 276. 40746-40754 (2001)
• [Publications] Yasukawa H, Hoshijima M, Yoshimura A, et al.: "SOCS3 is a biomechanical stress inducible gene that suppresses gp 130 mediated cardiac mediated hypertrophy and survival pathways"J.Clin.Invest.. 108. 1459-1467 (2001)
• [Publications] Suzuki A, Hanada T, Mitsuyama K, et al.: "CIS3/SOCS3/SSI3 plays a Negative Regiulatory Role in STAT3 Activation and Intestinal Inflammation"J.Exp.Med.. 193. 471-482 (2001)