lundi 28 janvier 2008

シンポジウム 「メチニコフの遺産・2008年」 で歴史を想う

 


イリヤ・メチニコフ(1845-1916)のノーベル賞受賞100周年を記念したシンポジウム ”Metchnikoff’s Legacy in 2008”が、晩年の研究生活を送ったパリのパスツール研究所で2008年4月28日-30日の3日間に亘って開かれた。私は昨年東京都医学研究機構を退職後、パリ大学で研究について考える生活を送っているのでその様子を覗いてみることにした。内容が多岐に渡るため、初日の歴史的なお話を中心に紹介したい。会の詳細は以下のページに(http://www.pasteur.fr/infosci/conf/sb/metchnikoff_2008/vf/index.html)、また2日目以降の内容についてはコーネル大学カール・ネイサン(Carl Nathan)教授のレポートを参照していただければ幸いである(Nature Immunology 9: 695-698, 2008)。

シンポジウムはジョンス・ホプキンス大学のアーサー・シルヴァーシュタイン(Arthur Silverstein)教授とボストン大学アルフレッド・タウバー(Alfred Tauber)教授の歴史的考察で始った。シルヴァーシュタイン氏はもともとは眼科学教授でありながら医学の歴史についても研究され、免疫学の分野では古典と言ってもよい "A History of Immunology" (1989年)を著している。私も随分お世話になった本である(余談だが、講演の後サインをいただいた)。氏は有名なメチニコフの写真を背景に、ゆったりとした調子で話を進めた。当時、炎症という現象が生体にとって害になると考えられていたが、メチニコフはヒトデで見出した貪食という現象をもとに、炎症は宿主の受身の対応ではなく積極的に対処している宿主にとって有益な反応であり、その中心に貪食細胞があると考えた。この考え方はドイツ学派には受け入れられず、彼が求めていたドイツでの就職は遂に成らなかった。1888年、彼が43歳の時にルイ・パスツールに呼ばれて創設されたばかりのパスツール研究所で仕事を開始し、1916年、71歳で亡くなるまで研究を続ける。

19世紀末から20世紀にかけての20年に亘って、免疫は細胞によるとするメチニコフの細胞説と免疫の主体は抗体であるとするポール・エーリッヒ(Paul Ehrlich)の液性説とが、フランスとドイツに別れて争った。しかしそれは不毛の争いではなく、むしろお互いが刺激し合い、新しい実験データ、新しいアイディアを生み出した実り多いものだったと結論している。その結果、1908年にはエーリッヒとともにノーベル賞を手に入れる。その後、貪食細胞には特異性がないこと、細胞の実験が非常に難しいこと、エーリッヒの提示した抗体産生のメカニズムを示す側鎖説の図の説得力、さらに決定打になったエミール・フォン・ベーリング(Emil von Behring)による血清療法の成功などが相まって、彼の説は次第に省みられなくなる。しかし、一世紀を経て彼の唱えた食作用、自然免疫という考え方が再び息を吹返してきている。

シルヴァーシュタイン氏は次のようなことを話して講演を終えた。「1960年代から70年代にかけて細胞性免疫の研究が盛んになった時に、メチニコフのことを持ち出す人はほとんどいなかった。また、1950年代のニールス・イェルネ(Niels Jerne)やマクファーレン・バーネット(Frank Macfarlane Burnet)が自然選択説やクローン選択説を提唱した時に、エーリッヒに対する賛辞(tribute)を捧げることはなかった。歴史を忘れないということは重要なことである」

タウバー氏はクリスティーの競売にかけられたという絵を示しながら、テンポ良く攻撃的に話を進めた。メチニコフが生まれたのは1845年で、1859年に発表されたダーウィンの「種の起源」の影響を同時代で受けている点が重要である。そのため彼は進化論の信奉者になっている。彼の求めた問は、どのようにして生体はその同一性・独自性(identity)を保っているのかというものであった。そのidentityは外界と協調関係(harmony)の上に成り立っているのではなく、むしろ外界との絶えざる戦い(disharmony)の中にあるのが正常の状態で、その監視役として貪食細胞があると考えていた。当時としては全く独創的な考えであった。タウバー氏自身は、免疫学が自己・非自己の認識に終始するある意味では閉ざされたシステムとしてあるのではなく、外界の他のシステムとも交わるオープンで全的な(holistic)システムとして捉えるべきではないのかと考えている様子が伝わってきた。

話の中で、メチニコフに纏わるエピソードをいくつか紹介していた。パスツール研究所での年収が1フランだったこと。紹介した研究経過でもわかるように、実際にドイツ人は彼のことを嫌っていて、研究所では両者が口もきかない時期があったこと。またノーベル賞授与に際して財団があげた理由がエーリッヒについては短いのに対し、メチニコフについては度を越えて長いものであったという。当時、非特異的な貪食細胞についての理解が、スマートな抗体による免疫には追いついていなかったということかもしれない。

それからもう一つ興味を惹いたのは、メチニコフとトルストイとの出会いである。1909年5月30日、クラスナヤ・ポリアナにあるトルストイの家でふたりは会う。この日は哲学的問題や社会問題について話が進み、メチニコフと彼の二度目の妻オルガにとって深い印象を残すことになる。しかし、それぞれの印象が異なっていた。神秘主義的哲学者のトルストイは言う。「私は事典を引いてみた。どれだけの蠅が分類されているのか当てて御覧なさい。何と7000もあるのだ。そんな状態で精神の本質的な問題について考える時間がどこにあるのだろうか」。一方、科学者メチニコフは、科学こそ病める人類を救い出す唯一のものであると考えていた。メチニコフがトルストイに対して尊敬の念を抱いていたのに対して、トルストイは科学ですべてが解決できると考えているメチニコフを浅はかな人間として捉えていたようだ。現在にも通じる視点の対立と言えなくもない。

シンポジウム初日の最後には、顕微鏡写真の開発者であるジャン・コマンドン(Jean Comandon, 1877-1970)という人の人生と実際に撮った映像が紹介されていた。彼の学位研究が梅毒の病原体トリポネーマで、その動きを捉えるために毎秒12-15コマで撮影することを思いついたのが、その後の運命を決めたようだ。その映像がパスツール研究所長エミール・ルー(Emil Roux)博士の眼に留まり、シネマトグラフィー室長として迎えられ、89歳で引退するまで写真を撮り続けた。彼はメチニコフと同じくパリ郊外のセーヴル(Sèvres)に居を構えていたが、その地で93歳の生涯を閉じている。紹介された映像は植物が花開く様、細胞や病原体の動き、寄生虫が貪食される様子など。今では珍しくないが、当時としては画期的なものだったに違いない。それまで忘れられていたかに見える時間的、空間的な観察の動画が最近では当たり前のように発表されるようになっているが、ある意味では一世紀を経て、彼と同じ発想が蘇っていると言えるのかもしれない。

今回の会議には日本から京都大学の長田重一教授が招待されていた。講演では、細胞死に陥った細胞を食細胞が貪食する機構について、マクロファージのあるサブセット(チオグリコレート刺激後、ランゲルハンス細胞、tingible-body Macrophageなど)で重要な分泌蛋白MFG-E8とresident MacrophageでのプレーヤーTim4という膜分子を中心に発表されていた。会の感想を伺ったところ、哲学的な含みのある発表がこれまでになく多いことに少々驚いておられた。確実に証拠がつかめたことについてだけが発表の対象と考えている多くの研究者と同じく、想像や形而上のお話にはついていけないという印象であった。私の方はこの手のお話を拒絶するというこれまでの姿勢が緩んでいることを感じることができた。最近の私の目から見ると、このような視点を持つ研究者を抱えていること、またその声を聞こうとする雰囲気があることは文化としての科学に奥行きを与えているように思えるのだが、いかがだろうか。





8th International Conference on Protein Phosphatases

November 12-14, 2008, Maebashi, Japan

Program

Wednesday, November 12

Opening Remarks
9:00-9:10 Mamoru Suzuki (President of Gunma University)
Toshiyuki Takeuchi (Director, IMCR, Gunma University)

Opening Lecture (Chair: Shinri Tamura)
9:10-10:00 Eisuke Nishida (Kyoto University)
ERK MAP kinase signaling: Regulatory mechanisms and function

Session I (Session chairs: David L. Brautigan and Reiko Sugiura)
10:00-10:20 Hiroshi Shima (Research Institute of Miyagi Cancer Center)
NIPP1 directs PP1 to dephosphorylate the essential pre-mRNA splicing factor, Sap155

10:20-10:50 Mathieu Bollen (University of Leuven, Belgium)
The expanding toolkit of protein phosphatase-1

10:50-11:20 Shirish Shenolikar (Duke-NUS Graduate Medical School, Singapore)
Proteasome degradation of GADD34: Novel mechanism for protein phosphatase-1 regulation

11:20-11:40 Noriyuki Sueyoshi (Kagawa University) Ca2+/calmodulin-dependent protein kinase phosphatase (CaMKP) is indispensable for normal embryogenesis in zebrafish, Danio rerio

11:40-11:55 Satoru Mochida (Cancer Research UK, United Kingdom) Identification of the PP2A heterotrimer complex that dephosphorylates the substrates of cyclin-dependent kinases in Xenopus egg extracts

12:00-13:30 Lunch

Session II (Session chairs: Shirish Shenolikar and Masato Ogata)
13:30-14:00 Susanne Klumpp (Westfaelische Wilhelms-University, Germany) Protein histidine phosphatase in vertebrates: A novel player in signal transduction

14:00-14:20 Shinri Tamura (Tohoku University)
Protein phosphatase 2Ce is an endoplasmic reticulum integral membrane protein that dephosphorylates the ceramide transport protein CERT to enhance its association with organelle membranes

14:20-14:50 David L. Brautigan (University of Virginia School of Medicine, USA)
Biochemistry and subunit organization of protein phosphatase-6

14:50-15:10 Reiko Sugiura (Kinki University)
Molecular genetic analysis of the calcineurin-mediated signaling pathways

15:10-15:25 Coffee Break

Session III (Session chairs: Mathieu Bollen and Toshio Watanabe)
15:25-15:55 David M. Virshup (Duke-NUS Graduate Medical School Singapore, Singapore)
Protein phosphatases in the Wnt signaling pathway

15:55-16:15 Tatsuya Maeda (The University of Tokyo)
Delayed activation kinetics ensures the signalling specificity of the hyperosmotic stress-responsive MAP kinase pathway in yeast

16:15-16:35 Satoshi Harashima (Osaka University)
Functional genomics of protein phosphatases in a single celled eukaryote

16:35-16:55 Katsumi Yamashita (Kanazawa University)
JNK- and SCFb-TrCP-mediated destruction of Cdc25B controls cell cycle arrest by non-genotoxic stress

16:55-17:10 Takayuki Murata (Aichi Cancer Center Research Institute)
TORC2 promotes EBV reactivation from latency via calcineurin

17:10-17:25 Shin-ichi Hisanaga (Tokyo Metropolitan University)
Effect of Pin-1 or microtubule-binding on dephosphorylation of FTDP-17 mutant Tau

17:30-18:50 Poster Session (I)

19:00-20:30 Banquet (at Tsutsuji-no-ma)


Thursday, November 13


Special Lecture (Chair: Takashi Matozaki)
9:00-9:50 Benjamin G. Neel (Ontario Cancer Institute, Canada)
Animal models of human disease-associated SHP2 (PTPN11) mutations

9:50-10:20 Group Photo

Session IV (Session chairs: Michel L. Tremblay and Masaharu Noda)
10:20-10:50 Anna A. DePaoli-Roach (Indiana University, USA)
Role of glycogen targeting subunits of PP1 in hormonal control of glycogen metabolism and glucose homeostasis

10:50-11:10 Seiji Inui (Kumamoto University)
Protein phosphatase 6 regulates the apoptotic signal transduction

11:10-11:30 Shigehisa Yanagi (Akita University / University of Miyazaki)
Analysis of Pten function in bronchioalveolar epithelium

11:30-11:50 Kazuya Mizuno (Tokyo Metropolitan Institute for Neuroscience)
Dual functions of SHP-1 in the regulation of mast cell signaling

11:50-13:30 Lunch
(Business meeting by the JAPPR committee at Oze-no-ma)

Session V (Session chairs: Anna A. DePaoli-Roach and Seiji Inui)
13:30-14:00 Nicholas K. Tonks (Cold Spring Harbor Laboratory, USA)
TBA

14:00-14:30 Michel L. Tremblay (McGill University, Canada)
Protein tyrosine phosphatases as tumor suppressors and oncogenes

14:30-14:50 Yoko Aoki (Tohoku University)
The Ras/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders

14:50-15:10 Masanori Hatakeyama (Hokkaido University)
SHP-2 phosphatase and human cancer

15:10-15:40 John L. Bixby (University of Miami Miller School of Medicine, USA)
Receptor tyrosine phosphatase PTPRO regulates the development and regeneration of sensory neurons

15:40-15:55 Coffee Break

Session VI (Session chairs: Nicholas K. Tonks and Masanori Hatakeyama)
15:55-16:15 Masaharu Noda (National Institute for Basic Biology)
Proteolytic processing of Ptprz and its potential role for nuclear signaling

16:15-16:35 Takashi Matozaki (Gunma University)
SAP-1 is a microvillus-specific protein tyrosine phosphatase that regulates intestinal tumorigenesis and inflammation

16:35-16:55 Seiji Torii (Gunma University)
A secretory granule-resident protein-tyrosine phosphatase phogrin regulates autocrine insulin signaling in pancreatic beta-cells

16:55-17:15 Tzu-Ching Meng (Academia Sinica, Taiwan)
A novel role of Drosophila protein tyrosine phosphatase dPTP61F in regulating actin organization

17:15-17:30 Suhad Ali (McGill University, Canada)
Role of SHP-2/Grb2 in prolactin signaling in mammary epithelial cell growth and differentiation

17:30-17:50 Hidetaka Yakura (University of Paris 1 Panthéon-Sorbonne, France) The phosphotyrosine signaling system: A view from the other side

17:50-19:00 Poster Session (II)


Friday, November 14

Session VII (Session chairs: Susanne Klumpp and Hiroshi Shima)
8:30-9:00 Dietmar Vestweber (Max Planck Institute of Molecular Biomedicine, Germany)
VE-PTP as regulator of endothelial cell contact integrity and vascular remodelling

9:00-9:30 Josef Krieglstein (Westfaelische Wilhelms-University, Germany)
Binding of ATP to growth factors as a prerequisite for their neuroprotective activity

9:30-9:50 Tomohiko Maehama (National Institute of Infectious Diseases)
Identification of a Ras-family GTPase as an indispensable signal
mediator for nutrient sensing and mTORC1 activation

9:50-10:10 Kensaku Mizuno (Tohoku University)
Molecular mechanisms of substrate recognition and
F-actin-mediated activation of cofilin-phosphatase slingshot-1 and its roles in cell migration and invasion

10:10-10:25 Noriko Uetani (McGill University, Canada)
Maturation of ureter-bladder connection and craniofacial development by LAR receptor protein-tyrosine phosphatases

Closing Remarks
10:25-10:35 Takashi Matozaki (Gunma University)




dimanche 27 janvier 2008

Scientific Activities (up to 2007)

ORGANIZATION OF SCIENTIFIC MEETINGS

1996.9
Organizer, TMIN Symposium/The Second International Symposium on Protein Phosphatases "Protein Phosphatases & Cellular Regulation" (Tokyo, Japan)

1997.10
Organizer, TMIN International Symposium 1997 "Kinases and Phosphatases in Lymphocyte and Neuronal Signaling" (Tokyo, Japan)

1998.11
Co-organizer, The Third International Symposium on Protein Phosphatases "Cellular Regulation by Protein Phosphatases" (Hiroshima, Japan)

2000.11
Co-organizer, The Fourth International Conference on Protein Phosphatases "Roles of Protein Phosphatases in Intracellular Signaling Systems" (Sendai, Japan)

2002.3
Co-organizer, The Fifth International Conference on "Protein Phosphatases and Cellular Regulation" (Okazaki, Japan)

2003.7
Co-organizer, The First Japanese Conference on “Protein Phosphatases” (Sapporo, Japan)

2004.2
Co-organizer, The 6th International Conference on “Protein Phosphatases & International Symposium on Nano-Biotechnology” (Okayama, Japan)


PUBLICATION

Papers


Ozawa T, Nakata K, Mizuno K & Yakura H (2007) Negative autoregulation of Src homology region 2-domain-containing phosphatase 1 in rat basophilic leukemia-2H3 cells. Int Immunol 19: 1049-1061

Mizuno K, Tagawa Y, Watanabe N, Ogimoto M & Yakura H (2005) SLP-76 is recruited to CD22 and dephosphorylated by SHP-1, thereby regulating B cell receptor-induced c-Jun N-terminal kinase activation. Eur J Immunol 35: 644-654

Ogimoto M, Ichinowatari G, Watanabe N, Tada N, Mizuno K & Yakura H (2004) Impairment of B cell receptor-mediated Ca2+ influx, activation of mitogen-activated protein kinases and growth inhibition in CD72-deficient BAL-17 cells. Int Immunol 16: 971-982

Shrivastava P, Katagiri T, Ogimoto M, Mizuno K & Yakura H (2004) Dynamic regulation of Src-family kinases by CD45 in B cells. Blood 103: 1425-1432

Mizuno K, Tagawa Y, Mitomo K, Watanabe N, Katagiri T, Ogimoto M & Yakura H (2002) Src homology region 2 domain-containing phosphatase 1 positively regulates B cell receptor-induced apoptosis by modulating association of B cell linker protein with Nck and activation of c-Jun NH2-terminal kinase. J Immunol 169: 778-786

Adachi T, Wienand J, Wakabayashi C, Yakura H, Reth M & Tsubata T (2001) SHP-1 requires inhibitory co-receptors to down-modulate B cell antigen receptor-mediated phosphorylation of cellular substrates. J Biol Chem 276: 26648-26655

Arimura Y, Ogimoto M, Mitomo K, Katagiri T, Yamamoto K, Volarevic S, Mizuno K & Yakura H (2001) CD45 is required for CD40-induced inhibition of DNA synthesis and regulation of c-Jun NH2-terminal kinase and p38 in BAL-17 B cells. J Biol Chem 276: 8550-8556

Ogimoto M, Arimura Y, Katagiri T, Mitomo K, Woodgett JR, Nebreda AR, Mizuno K & Yakura H (2001) Opposing regulation of B cell receptor-induced activation of mitogen-activated protein kinases by CD45. FEBS Lett 490: 97-101

Kumanogoh A, Watanabe C, Lee I, Wang X, Shi W, Araki H, Hirata H, Iwahori K, Uchida J, Yasui T, Matsumoto M, Yoshida K, Yakura H, Pan C, Parnes JR & Kikutani H (2000) Identification of CD72 as a lymphocyte receptor for the class IV semaphorin CD100: A novel mechanism for regulating B cell signaling. Immunity 13: 621-631

Mizuno K, Tagawa Y, Mitomo K, Arimura Y, Hatano N, Katagiri T, Ogimoto M & Yakura H (2000) Src homology 2 (SH2) domain-containing phosphatase-1 dephosphorylates B cell linker protein/SH2 domain leukocyte protein of 65 kDa and selectively regulates c-Jun NH2-terminal kinase activation in B cells. J Immunol 165: 1344-1351

Uetani N, Kato K, Ogura H, Mizuno K, Kawano K, Mikoshiba K, Yakura H, Asano M & Iwakura Y (2000) Impaired learning with enhanced hippocampal long-term potentiation in PTPδ-deficient mice. EMBO J 19: 2775-2785

Adachi T, Wakabayashi C, Yakura H & Tsubata T (1999) CD72 negatively regulates signaling through the antigen receptor of B cells. J Immunol 164: 1223-1229

Katagiri T, Ogimoto M, Hasegawa K, Arimura Y, Mitomo K, Okada M, Clark MR, Mizuno K & Yakura H (1999) CD45 negatively regulates Lyn activity by dephosphorylating both positive and negative regulatory tyrosine residues in immature B cells. J Immunol 163: 1321-1326

Hasegawa K, Yajima H, Katagiri T, Ogimoto M, Arimura Y, Mitomo K, Mashima K, Mizuno K & Yakura H (1999) Requirement of PEST domain tyrosine phosphatase PEP in B cell antigen receptor-induced growth arrest and apoptosis. Eur J Immunol 29: 887-896

Adachi T, Flaswinkel H, Yakura H, Reth M & Tsubata T (1998) The B cell surface protein CD72 recruits the tyrosine phosphatase SHP-1 upon tyrosine phosphorylation. J Immunol 160: 4662-4665

Mizuno K, Katagiri T, Maruyama E, Hasegawa K, Ogimoto M & Yakura H (1997) SHP-1 is involved in neuronal differentiation of P19 embryonic carcinoma cells. FEBS Lett 417: 6-12

Nomura T, Han H, Howard MC, Yagita H., Yakura H, Honjo T & Tsubata T (1996) Antigen receptor-mediated B cell death is blocked by signaling via CD72 or treatment with dextran sulfate and is defective in autoimmunity-prone mice. Int Immunol 8: 867-875

Mizuno K, Katagiri T, Hasegawa K, Ogimoto M & Yakura H (1996) Hematopoietic cell phosphatase, SHP-1, is constitutively associated with the SH2 domain-containing leukocyte protein, SLP-76, in B cells. J Exp Med 184: 457-463

Katagiri T, Ogimoto M, Hasegawa K, Mizuno K & Yakura H (1995) Selective regulation of Lyn tyrosine kinase by CD45 in immature B cells. J Biol Chem 270: 27987-27990

Ogimoto M, Katagiri T, Mashima K, Hasegawa K, Mizuno K & Yakura H (1995) Antigen receptor-initiated growth inhibition is blocked in CD45-loss variants of a mature B lymphoma, with limited effects on apoptosis. Eur J Immunol 25: 2265-2271

Ariyama T, Hasegawa K, Inazawa J, Mizuno K, Ogimoto M, Katagiri T & Yakura H (1995) Assignment of the human protein tyrosine phosphatase, receptor-type, zeta (PTPRZ) gene to chromosome band 7q31.3. Cytogenet Cell Genet 70: 52-54

Mizuno K, Hasegawa K, Ogimoto M, Katagiri T & Yakura H (1994) Developmental regulation of gene expression for the MPTPδ isoforms in the central nervous system and the immune system. FEBS Lett 355: 223-228

Ogimoto M, Katagiri T, Mashima K, Hasegawa K, Mizuno K & Yakura H (1994) Negative regulation of apoptotic death in immature B cells by CD45. Int Immunol 6: 647-654

Ogimoto M, Katagiri T, Hasegawa K, Mizuno K & Yakura H (1993) Induction of CD45 isoform switch in murine B cells by antigen receptor stimulation and by phorbol myristate acetate and ionomycin. Cell Immunol 151: 97-109

Mizuno K, Hasegawa K, Katagiri T, Ogimoto M, Ichikawa T & Yakura H (1993) MPTPδ, a putative murine homolog of HPTPδ, is expressed in specialized regions of the brain and in the B-cell lineage. Mol Cell Biol 13: 5513-5523

Hasegawa K, Ariyama T, Inazawa J, Mizuno K, Ogimoto M, Katagiri T & Yakura H (1993) Chromosomal assignment of the gene for protein tyrosine phosphatase HPTPδ. Jpn J Cancer Res 84: 1219-1222

Ogimoto M, Mizuno K, Tate G, Takahashi H, Katagiri M, Hasegawa K & Yakura H (1992) Regulation of lipopolysaccharide- and IL-4-induced immunoglobulin heavy chain gene activation: differential roles for CD45 and Lyb-2. Int Immunol 4: 651-659

Ashida T, Kubo K, Kawabata I, Katagiri M, Ogimoto M & Yakura H (1990) Signal transduction mechanisms of Ia induction in B cells by interleukin 4 and immunoglobulin receptors. Cell Immunol 126: 233-238

Kobata T, Yagita H, Matsuda H, Tansyo S, Yakura H, Katagiri M & Okumura K (1990) A novel homodimeric molecule involved in human T cell activation. J Immunol 144: 830-835

Daita G, Yonemasu Y, Ishikawa M, Shimizu T & Yakura H (1989) Intracranial malignant teratoma diagnosed in a fetus. Neurol Med Chir 29: 1026-1029

Yakura H, Ashida T, Kawabata I & Katagiri M (1989) Alleviation of autoimmunity in BXSB mice by monoclonal alloantibody to Ly-5 (CD45). Eur J Immunol 19: 1505-1508

Ashida T, Yakura H, Kawabata I, Murakami M & Katagiri M (1988) Structural features of the Lyb-2 molecule. Immunogenet 28: 286-288

Yakura H, Kawabata I, Ashida T, Shen FW & Katagiri M (1986) A role for Lyb-2 in B cell activation mediated by a B cell stimulatory factor. J Immunol 137: 1475-1481

Yakura H, Kawabata I, Shen FW & Katagiri M (1986) Selective inhibition of lipopolysaccharide-induced IgG response by monoclonal Ly-5 antibody. J Immunol 136: 2729-2733

Yakura H, Shen FW, Bourcet E & Boyse EA (1983) On the function of Ly-5 in the regulation of antigen-driven B cell differentiation. Comparison and contrast with Lyb-2. J Exp Med 157: 1077-1088

Yakura H, Shen FW, Bourcet E & Boyse EA (1982) Evidence that Lyb-2 is critical to specific activation of B cells before they become responsive to T cell and other signals. J Exp Med 155: 1309-1316

Yakura H, Shen FW, Kaemmer M & Boyse EA (1981) Lyb-2 system of mouse B cell. Evidence for a role in the generation of antibody-forming cells. J Exp Med 153: 129-135

Yakura H, Shen FW, Boyse EA & Tang L (1980) The Lyb-2 phenotype of hemolytic PFC. Immunogenet 10: 603-605

Sasazuki T, McMichael A, Payne R, McDevitt HO, Yakura H, Wakisaka A, Aizawa M & Itakura K (1977) An HLA-D specificity found in the Japanese population. Tissue Antigens 9: 62-65

Yakura H, Wakisaka A, Aizawa M, Itakura K, Tagawa Y & Sugiura S (1976) HLA-D antigen of Japanese origin (LD-Wa) and its association with Vogt-Koyanagi-Harada syndrome. Tissue Antigens 8: 35-42

Wagatsuma Y, Yakura H, Nakayama E, Wakisaka A, Aizawa M, Miyata M, Matsuyama R, Sato M & Itakura K (1976) Inheritance of asthma in families and its linkage to HLA haplotypes. Acta Allergol 31: 455-462

Tagawa Y, Sugiura S, Yakura H, Wakisaka A, Aizawa M & Itakura K (1976) HLA and Vogt-Koyanagi-Harada syndrome. N Eng J Med 295: 173

Yakura H, Wakisaka A, Fujimoto S & Itakura K (1974) Hereditary ataxia and HL-A genotypes. N Eng J Med 291: 154-155

Nakayama E, Itakura K, Yakura H, Aizawa M, Kuroda M & Hanada K (1974) Sa 1, a possible new HL-A specificity found in the Japanese population. Vox Sang 27: 134-140

Reviews

Yakura H (1998) Phosphatases and kinases in lymphocyte signaling. Immunol Today 19: 198-2016

Yakura H (1994) The role of protein tyrosine phosphatases in lymphocyte activation and differentiation. Crit Rev Immunol 14: 311-336

Shen FW, Yakura H & Tung JS (1982) Some compartments of B cell differentiation. Immunol Rev 69: 69-80

Itakura K, Yakura H, Nakayama E & Aizawa M (1975) HL-A and MLC antigens in the Japanese population. Keio J Med 24: 377-391

Books

Yakura H (editor) (1997) Kinases and Phosphatases in Lymphocyte and Neuronal Signaling. Springer-Verlag, Tokyo, Japan

Yakura H, Katagiri T, Ogimoto M, Hasegawa K, Arimura Y, Mitomo K & Mizuno K (1997) Protein tyrosine phosphatases in B lymphocyte signaling. In "Kinases and Phosphatases in Lymphocyte and Neuronal Signaling" (ed, Yakura H) Springer-Verlag, Tokyo, Japan. pp.134-146

Mizuno K, Katagiri T, Hasegawa K, Arimura Y, Mitomo K, Ogimoto M & Yakura H (1997) Possible involvement of Src homology region 2 domain-containing phosphatase-1, SHP-1, in neuronal differentiation. In "Kinases and Phosphatases in Lymphocyte and Neuronal Signaling" (ed, Yakura H) Springer-Verlag, Tokyo, Japan. pp. 310-311

Uetani N, Asano M, Mizuno K, Yakura H & Iwakura Y (1997) Targeted disruption of the murine protein tyrosine phosphatase delta (MPTPδ) gene results in growth retardation and behavioral abnormalities. In "Kinases and Phosphatases in Lymphocyte and Neuronal Signaling" (ed, Yakura H) Springer-Verlag, Tokyo, Japan. pp. 313-314

Hasegawa K, Katagiri T, Ogimoto M, Arimura Y, Mizuno K, Mitomo K & Yakura H. Role of PEST domain tyrosine phosphatase PEP in B cell antigen receptor-induced signaling. In "Kinases and Phosphatases in Lymphocyte and Neuronal Signaling" (ed, Yakura H) Springer-Verlag, Tokyo, Japan 1997. pp. 325-326

Katagiri T, Ogimoto M, Hasegawa K, Arimura Y, Mitomo K, Mizuno K & Yakura H. CD45 differentially regulates B cell antigen receptor-mediated tyrosine phosphorylation in immature and mature B cell. In "Kinases and Phosphatases in Lymphocyte and Neuronal Signaling" (ed, Yakura H) Springer-Verlag, Tokyo, Japan 1997. pp. 328-329

Ogimoto M, Arimura Y, Mitomo K, Katagiri T, Hasegawa K, Mizuno K & Yakura H. Regulation of MAP kinases and NF-κB activation by CD45 in WEHI-231 and BAL-17 B cells. In "Kinases and Phosphatases in Lymphocyte and Neuronal Signaling" (ed, Yakura H) Springer-Verlag, Tokyo, Japan 1997. pp. 330-331

Arimura Y, Ogimoto M, Mitomo K, Katagiri T, Hasegawa K, Mizuno K & Yakura H. Role of CD45 in CD40 signaling in mature B lymphoma cells. In "Kinases and Phosphatases in Lymphocyte and Neuronal Signaling" (ed, Yakura H) Springer-Verlag, Tokyo, Japan 1997. pp. 334-335

Yakura H, Tate G, Sakata H, Kawabata I, Ashida T & Katagiri M (1988) Regulation of lipopolysaccharide-induced B cell differentiation by Ly-5 and Lyb-2 molecules. In “Lymphocyte
Activation and Differentiation” (eds, Mani JC, & Dornand J) Walter de Gruyter & Co, Berlin, Germany. pp. 595-598

Murakami M, Miyokawa N, Yakura H, Ikeda H & Katagiri M (1986) A non-DR and –DQ class II molecule detected by monoclonal antibody AS-9C4. In ”HLA in Asia-Oceania 1986” (ed, Aizawa M) Hokkaido Univ Press, Sapporo, Japan. pp. 439-447

Aizawa M, Yakura H, Wakisaka A, Maruyama N, Kimura S, Moriuchi J, Kuroda M, Hamatake K & Itakura K (1975) Analysis of the Workshop sera against Japanese permanent panel. In “Histocompatibility Testing 1975” (ed, Kissmeyer-Nielsen F) Munksgaard, Copenhagen, Denmark. pp. 136-142

<Articles & Books in Japanese not listed>

SYMPOSIA

2006.5.15
SHP-1 dephsohprylates SHP-1 and SLP-76, thereby inactivating SHP-1 in mast cells. Block Symposium "Mast Cells and Basophils", Immunology 2006. (Bonston, MA, USA)

2005.10.21
Regulation of mast cell activation by protein tyrosine phosphatase SHP-1. Symposium on "Novel signaling pathways involved in allergic reactions", The 55th Japanese Society of Allergology. (Morioka, Japan)

2005.7.11
PTPε negatively regulates FcεRI-mediated mast cell activation. Europhosphatases Conference 2005. "The Biology of Phosphatases" (Cambridge, UK)

2005.4.3
Inhibitory regulation of FcεRI-mediated mast cell functions by SHP-1. Block Symposium "Mast cells", Experimental Biology 2005. The 92st AAI Meeting. (San Diego, CA, USA)

2004.12.2
Regulation of mast cell activation by protein tyrosine phosphatases. Symposium on “Role of protein phosphatases in the immune signaling”, The 34th Japanese Society of Immunology (Sapporo, Japan)

2004.2.18
Regulation of lymphocyte and mast cell signaling by protein tyrosine phosphatases. The Sixth International Conference on “Protein Phosphatases and International Symposium on Nano-Biothechnology” (Okayama, Japan)

2002.10.17
Present state and future direction in protein phosphatase research. Symposium on "New Developments in Protein Phosphatase Research", The 72nd Japanese Biochemical Society (Yokohama, Japan)

2002.5.14
Regulation of mast cell activation by protein tyrosine phosphatases. Osaka University Medical School Symposium “Biology of Mast Cells and Basophils” (Osaka, Japan)

2002.3.14
Novel, dynamic regulation of Src-family tyrosine kinases by CD45. The Fifth International Conference on “Protein Phosphatases and Cellular Regulation” (Okazaki, Japan)

2000.11.12
Dynamic regulation of lymphocyte signaling by protein tyrosine phosphatase CD45. The fourth International Conference on "Roles of Protein Phosphatases in Intracellular Signaling Systems" (Sendai, Japan)

2000.6.4
Role of protein tyrosine phosphatases in lymphocyte signaling and brain functions. International Symposium on “Neuronal Signaling and Protein Phosphorylation-Dephosphorylation” (Fukuoka, Japan)

1999.12.2
Inhibitory co-receptors on B lymphocytes. Symposium "Inhibitory receptors and signals in the immune regulation", The 29th Japanese Society for Immunology (Kyoto, Japan)

1999.10.7
Regulation of Src-family tyrosine kinases by CD45. Symposium on "Regulation of Signal Transduction by Protein Phosphatases", The 72nd Japanese Biochemical Society (Yokohama, Japan)

1999.10.7
Role of PTPδ in neuronal function. Symposium on "Regulation of Signal Transduction by Protein Phosphatases", The 72nd Japanese Biochemical Society (Yokohama, Japan)

1999.5.15
Regulation of Src-family tyrosine kinases by CD45 in B cells. Cold Spring Harbor Meeting on "Tyrosine Phosphorylation & Cell Signalling" (Cold Spring Harbor, NY, USA)

1999.4.20
Differential regulation of MAPKs by CD45 in two different B cell lines. Block Symposium "B Lymphocyte Activation", Experimental Biology '99 (Washington, DC, USA)

1999.4.18
Requirement of PEST domain tyrosine phosphatase PEP in BCR-induced growth arrest and apoptosis. Block Symposium "B Lymphocyte Apoptosis", Experimental Biology '99 (Washington, DC, USA)

1998.11.21
Targeted disruption of the MPTPδ gene results in growth retardation and abnormal behavior. The 3rd International Symposium on "Cellular Regulation by Protein Phosphatases" (Hiroshima, Japan)

1998.11.21
The role of protein tyrosine phosphatases in B lymphocyte signaling. The 3rd International Symposium on "Cellular Regulation by Protein Phosphatases" (Hiroshima, Japan)

1998.10.17
Regulation of mast cell activation by protein tyrosine phosphatases. Symposium on "The New Development in Protein Phosphatases", The 71st Japanese Biochemical Society (Nagoya, Japan)

1997.10.16
Possible involvement of Src homology region 2 domain-containing phosphatase-1, SHP-1, in neuronal differentiation. The 13th TMIN International Symposium on "Kinases and Phosphatases in Lymphocyte and Neuronal Signaling" (Tokyo, Japan)

1997.10.15
Regulation of B cell signaling by protein tyrosine phosphatases. The 13th TMIN International Symposium on "Kinases and Phosphatases in Lymphocyte and Neuronal Signaling" (Tokyo, Japan)

1997.9.24
Regulation of neuronal cell differentiation by PTP. Minisymposium on "Protein Phosphatases in Signal Transduction Pathways", The 70th Japanese Biochemical Society (Kanazawa, Japan)

1996.11.26
Tyrosine phosphatases in B cell antigen receptor-mediated signaling. Symposium on "Molecular Mechanisms of Antigen Receptor Signals", The 26th Japanese Society for Immunology (Yokohama, Japan)

1996.9.27
Negative regulation of Lyn tyrosine kinase by CD45 in immature B cells. TMIN Symposium on "Protein Phosphatases and Cellular Regulation" (Tokyo, Japan)

1996.9.26
Possible involvement of protein tyrosine phosphatases in neuronal differentiation of P19 embryonic carcinoma cells. TMIN Symposium on "Protein Phosphatases and Cellular Regulation" (Tokyo, Japan)

1994.9.7
Search for substrates of CD45 in immature B cells. Colloquium on "Growth and Death of Lymphocytes", The 67th Japanese Biochemical Society (Osaka, Japan)

1994.5.28
Tyrosine phosphatases involved in the regulation of the immune system. Symposium on "Regulation of Cellular Functions and Protein Phosphatases", The 60th Japanese Biochemical Society in Tohoku (Akita, Japan)

1994.4.28
Role for CD45 in B cell activation and inactivation. Minisymposium on "Molecular Aspects of B Cell Development and Differentiation", Experimental Biology '94 (Anaheim, CA)

1987.11
Regulation of B cell growth and differentiation by Lyb-2 and Ly-5. “Lecture A of Japanese Society of Pathology” (Tokyo, Japan)

1986.1
Analysis of B cell differentiation by anti-receptor antibodies. “Symposium of Ministry of Health and Welfare of Japan” (Tokyo, Japan)

1985.5
Two molecules involved in B cell activation: Lyb-2 and Ly-5. “First Symposium of Japanese Society for Immunology” (Fukuoka, Japan)

1985.4
Lyb-2 as a possible B cell growth factor (BCGF) I receptor. Minisymposium “B cell activation”, American Association of Immunologists

SEMINARS

2006.2.16
National University of Singapore, Singapore
“Regulation of lymphocyte and mast cell activation by protein tyrosine phosphatases”

2005.7.4
Hôpital Necker-Enfants Malades - Paris V, Paris, France
“Régulation de l’activation des lymphocytes et des mastocytes par protéine-tyrosine phosphatases”

2005.6.28
l’Institut de Signalisation et Innovation Thérapeutique - Université Paris-Sud XI., Châtenay-Malabry, France
“Régulation de l’activation des lymphocytes et des mastocytes par protéine-tyrosine phosphatases”

2005.6.23
Institut Pasteur, Paris, France
“Regulation of lymphocyte and mast cell signaling by tyrosine phosphatases”

2002.4.10
Tokyo University of Agriculture and Technology, Tokyo, Japan
“Regulation of two biological systems by protein tyrosine phosphatases”

2001.7.20
Institut Pasteur, Paris, France
“Role of protein tyrosine phosphatases in lymphocyte signaling”

2001.7.13
University of Rijeka, Rijeka, Croatia
“Regulation of lymphocyte signaling by protein tyrosine phosphatases”

2001.5.22
McGill Cancer Centre, McGill University, Montreal, Canada
“Regulation of lymphocyte signaling by CD45”

2000.1.27
Asahikawa Medical College, Asahikawa, Japan
“Lymphocyte signaling and tyrosine phosphatases”

1999.6.1
Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA
“Protein tyrosine phosphatases in lymphocyte signal transduction”

1999.5.10
University of Texas MD Anderson Cancer Center, Houston, USA
“Protein tyrosine phosphatases in B cell fate determination”

1999.4.14
Pennsylvania State University College of Medicine, Hershey, USA
“Protein tyrosine phosphatases regulating B cell receptor signaling”

1999.4.12
Indiana University School of Medicine, Indianapolis, USA
“Protein tyrosine phosphatases that determine lymphocyte fate”

1999.3.8
Institute of Immunological Science, Hokkaido University, Sapporo, Japan
“Regulatory mechanisms of tyrosine phosphatases in lymphocyte signal transduction”

1998.10.30
Institute of Molecular and Cell Biology, National University of Singapore, Singapore
“The role of protein tyrosine phosphatases in lymphocyte signaling”

1998.10.23
National Institute for Basic Biology, Okazaki, Japan
“Regulation of the immune system by protein tyrosine phosphatases”

1998.3.12
Research Laboratory, Otsuka America Pharmaceutical, Inc., Bethesda, USA
“Protein tyrosine phosphatases in lymphocyte signaling”

1998.1.30
Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Japan
“Regulation of lymphocyte signal transduction by tyrosine phosphatases”

1998.1.27
Okayama University School of Medicine, Okayama, Japan
“Lymphocyte signal transduction and protein tyrosine phosphatases”

1997.7.24
Institute of Immunology, University of Heidelberg, Heidelberg, Germany
“Protein tyrosine phosphatases and B cell signal transduction”

1997.7.18
Max-Planck Institute for Immunobiology, Freiburg, Germany
“Protein tyrosine phosphatases in B lymphocyte signaling”

1997.7.16
Basel institute for Immunology, Basel, Switzerland
“Protein tyrosine phosphatases in BCR signal transduction”

1997.7.15
Friedrich Miescher Institute, Basel, Switzerland
“Regulation of lymphocyte signaling by protein tyrosine phosphatases”

1997.7.2
Otsuka Pharmaceutical Co., Tokushima, Japan
“Signal transduction of B lymphocytes and protein tyrosine phosphatases”

1997.6.26
Faculty of Pharmaceutical Sciences, Osaka University, Osaka, Japan
“Mechanisms of B cell activation”

1997.5.14
Babraham Institute, Cambridge, UK
“Regulation of B cell signaling by protein tyrosine phosphatases”

1995.8.4
University of Iowa College of Medicine, Iowa City, USA
“Regulation of B cell signal transduction by protein tyrosine phosphatases”

1994.10 .12
Institute of Immunological Science, Hokkaido University, Sapporo, Japan
“Regulation of the immune system by protein tyrosine phosphatases”

1994.1.14
Institute of Medical Science, University of Tokyo, Tokyo, Japan
“Regulation of lymphocyte activation by protein tyrosine phosphatases”

1992.7.31
Asahikawa Medical College, Asahikawa, Japan
“Regulation of immune and nervous systems by receptor-type protein tyrosine phosphatases”

1992.7.27
National Jewish Center for Immunology and Respiratory Medicine, Denver, USA
“Receptor-type protein tyrosine phosphatases expressed in the immune and central nervous systems”

1991.5.3
University of Texas MD Anderson Cancer Center, Houston, USA
“Regulatory mechanisms of B lymphocyte differentiation by CD45, a protein tyrosine phosphatase, and Lyb-2”

1991.4.29
University of Miami School of Medicine, Miami, USA
“Regulation of B cell differentiation by Lyb-2 and a transmembrane tyrosine phosphatase CD45 ”

1989.10 .23
Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
“B cell activation and immunological abnormalities”

1989.8.8
Institute of Immunology, Johannes Gutenberg University, Mainz, Germany
“Regulation of antibody class by differentiation antigens and its clinical relevance”

1989.5.17
Allergy Consortium, Chiba University, Chiba, Japan
“Regulation of antibody class switch and treatment of autoimmune disorders”

1989.2.15
Institute of Immunological Science, Hokkaido University, Sapporo, Japan
“Regulatory mechanisms of B cell differentiation and potential therapeutic strategies for autoimmune diseases”

1984.8.29
Clinical Research Centre, Harrow, UK
“Differentiation antigens that regulate B cell differentiation”

1983.1.11
State University of New York, Stony Brook, USA
“Mechanisms of B lymphocyte activation”

1982.9.10
Institute of Immunology, Chiba University, Chiba, Japan
“Mechanisms of lymphocyte differentiation mediated by B cell differentiation antigens”

1982.5.26
Downstate Medical Center, State University of New York, Brooklyn, USA
“Regulation of B cell differentiation by non-immunoglobulin allotypic molecules”

1978.1.3
Harvard Medical School, Boston, USA
“Role of T lymphocytes in the immune response to Listeria monocytogenes