Tumor-stroma interaction mediated by proteases

• Project/Area Number: 17014019
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: The University of Tokyo
• Principal Investigator: SEIKI Motoharu The University of Tokyo, 医科学研究所, 教授 (10154634)
• Co-Investigator(Kenkyū-buntansha): KOSIKAWA Naohiko 東京大学, 医科学研究所, 講師 (70334282) ; 後藤 勇 東京大学, 医科学研究所, 助教 (40323638)
• Co-Investigator(Renkei-kenkyūsha): GOTO Isamu (40323638)
• Project Period (FY): 2005 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥339,200,000 (Direct Cost: ¥339,200,000); Fiscal Year 2009: ¥68,700,000 (Direct Cost: ¥68,700,000); Fiscal Year 2008: ¥68,700,000 (Direct Cost: ¥68,700,000); Fiscal Year 2007: ¥68,900,000 (Direct Cost: ¥68,900,000); Fiscal Year 2006: ¥68,900,000 (Direct Cost: ¥68,900,000); Fiscal Year 2005: ¥64,000,000 (Direct Cost: ¥64,000,000)
• Keywords: 膜型プロテアーゼ / 腫瘍微小環境 / 浸潤 / MT1-MMP / p27RE-Rho / Rho活性化 / 浸潤突起 / HIF-1 / マクロファージ / FIH-1 / Mint3 / ラミニン332 / 腫瘍血管新 / 生モノクローナル抗体 / コラーゲン分解 / 腫瘍形成 / MMP-2 / コラーゲン / 腫瘍抑制 / MMP / CD44

Research Abstract

MT1-MMP is an integral membrane protease that acts as an important component of cellular machinery promoting invasion and tumor growth. It is also a potent modulator of tumor microenvironment. In this study, we identified substrates of MT1-MMP, analyzed regulation of the proteolytic events, surveyed proteins that bind MT1-MMP, and studied non-protease activity of MT1-MMP. We also validated the potential therapeutic value of MT1-MMP as a molecule target for development of therapeutic strategies.

Research Products

• [Journal Article] A novel protein associated with membrane-type 1 matrix metalloproteinase binds p27 (kip1) and regulates RhoA activation, actinremodeling, and matrigel invasion. (2009)
  • Author(s): Hoshino, D., T.Tomari, M.Nagano, N.Koshikawa, M.Seiki.
  • Journal Title: J BiolChem 284 Pages: 27315-27326
• [Journal Article] Identification and characterization of Lutheran blood group glycoprotein as a new substrate of membrane-type 1 matrix metalloproteinase 1 (MT1-MMP) : asystemic whole cell analysis of MT1-MMP-associating proteins in A431 cells. (2009)
  • Author(s): Niiya, D., N.Egawa, T.Sakamoto, Y.Kikkawa, T.Shinkawa, T.Isobe, N.Koshikawa, M.Seiki.
  • Journal Title: J Biol Chem 284 Pages: 27360-27369
• [Journal Article] Mint3enhances the activity of hypoxia-inducible factor-1 (HIF-1) in macrophages by suppressing the activity of factor inhibiting HIF-1. (2009)
  • Author(s): Sakamoto, T., M.Seiki.
  • Journal Title: J Biol Chem 284 Pages: 30350-30359
• [Journal Article] High throughput analysis of proteins associating with a proinvasive MT1-MMP in human malignant melanoma A375 cells. (2009)
  • Author(s): Tomari, T., N.Koshikawa, T.Uematsu, T.Shinkawa, D.Hoshino, N.Egawa, T.Isobe, M.Seiki.
  • Journal Title: Cancer Sci 100 Pages: 1284-1290
  • NAID: 10027192295
• [Journal Article] A novel protein associated with membrane-type 1 matrix metalloproteinase binds p27(kip1) and regulates RhoA activation, actin remodeling, and matrigel invasion (2009)
  • Author(s): 星野, 他4名
  • Journal Title: J Biol Chem Volume: 284 Pages: 27315-26
  • Peer Reviewed
• [Journal Article] Identification and characterization of Lutheran blood group glycoprotein as a new substrate of membrane-type 1 matrix metalloproteinase 1 (MT1-MMP) : a systemic whole cell analysis of MT1-MMP-associating proteins in A431 cells (2009)
  • Author(s): 新谷, 他7名
  • Journal Title: J Biol Chem Volume: 284 Pages: 27360-9
  • Peer Reviewed
• [Journal Article] Mint3 enhances the activity of hypoxia-inducible factor-1(HIF-1) in macrophages by suppressing the activity of factor inhibiting HIF-1 (2009)
  • Author(s): 坂本、清木
  • Journal Title: J Biol Chem Volume: 284 Pages: 30350-9
  • Peer Reviewed
• [Journal Article] Spontaneous transformation of human granulosa cell tumours into an aggressive henotype : a metastasis model cell line. (2008)
  • Author(s): Imai, M., M.Muraki, K.Takamatsu, H.Saito, M.Seiki, Y.Takahashi.
  • Journal Title: BMC Cancer 8 Pages: 319-319
• [Journal Article] The second dimer interface of MT1-MMP, the transmembrane domain, is essential for ProMMP-2 activation on the cell surface. (2008)
  • Author(s): Itoh, Y., N.Ito, H.Nagase, M.Seiki.
  • Journal Title: J Biol Chem 283 Pages: 13053-13062
• [Journal Article] Development of a new tracking tool for the human monomeric laminin-gamma 2 chain in vitro and in vivo. (2008)
  • Author(s): Koshikawa, N., T.Minegishi, K.Nabeshima, M.Seiki.
  • Journal Title: Cancer Res 68 Pages: 530-536
• [Journal Article] Development of a new tracking tool for the human monomeric laminin-gamma 2 chain in vitro and in vivo (2008)
  • Author(s): Koshikawa, N., Seiki, M., (他2名)
  • Journal Title: Cancer Research 68 Pages: 530-536
  • Peer Reviewed
• [Journal Article] Regulated nucleo-cytoplasmic shuttling of human aci-reductone dioxygenase (hADI1) and its potential role in mRNA processing. (2007)
  • Author(s): Gotoh, I., T.Uekita, M.Seiki.
  • Journal Title: Genes Cells 12 Pages: 105-117
• [Journal Article] Establishment of an MT4-MMP-deficient mouse strain representing an efficient tracking system for MT4-MMP/MMP-17 expression in vivo using beta-galactosidase. (2007)
  • Author(s): Rikimaru, A., K.Komori, T.Sakamoto, H.Ichise, N.Yoshida, I.Yana, M.Seiki.
  • Journal Title: Genes Cells 12 Pages: 1091-1100
• [Journal Article] Stroma-derived matrix metalloproteinase (MMP)-2 promotes membrane type 1-MMP-dependent tumor growth in mice. (2007)
  • Author(s): Taniwaki, K., H.Fukamachi, K.Komori, Y.Ohtake, T.Nonaka, T.Sakamoto, T.Shiomi, Y.Okada, T.Itoh, S.Itohara, M.Seiki, I.Yana.
  • Journal Title: Cancer Res 67 Pages: 4311-4319
• [Journal Article] Crosstalk between neovessels and mural cells directs the site-specific expression of MT1-MMP to endothelial tip cells. (2007)
  • Author(s): Yana, I., H.Sagara, S.Takaki, K.Takatsu, K.Nakamura, K. Nakao, M.Katsuki, S.Taniguchi, T.Aoki, H.Sato, S.J.Weiss, M.Seiki.
  • Journal Title: J Cell Sci 120 Pages: 1607-1614
• [Journal Article] Stroma-derived matrix metalloproteinase (MMP)-2 promotes membrane type 1-MMP-dependent tumor growth in mice (2007)
  • Author(s): Taniwaki, K., Seiki, M., (他10名)
  • Journal Title: Cancer Research 67 Pages: 4311-4319
  • Peer Reviewed
• [Journal Article] Crosstalk between neovessels and mural cells directs the site-specific expression of MT1-MMP to endothelial tip cells (2007)
  • Author(s): Yana, I., Seiki, M., (他10名)
  • Journal Title: J Cell Sci 120 Pages: 1607-1614
  • Peer Reviewed
• [Journal Article] Establishment of an MT4-MMP-deficient mouse strain representing an efficient tracking system for MT4-MMP/MMP-17 expression in vivo using beta-galactosidase. (2007)
  • Author(s): Rikimaru, A.., Seiki, M., (他5名)
  • Journal Title: Cancer Research 12 Pages: 1091-1100
  • Peer Reviewed
• [Journal Article] Membrane type 1 matrix metalloproteinase (MT1-MMP/MMP-14) cleaves and releases a 22-kDa extracellular matrix metalloproteinase inducer (EMMPRIN) fragment from tumor cells. (2006)
  • Author(s): Egawa, N., N.Koshikawa, T.Tomari, K.Nabeshima, T.Isobe, M.Seiki.
  • Journal Title: J Biol Chem 281 Pages: 37576-37585
• [Journal Article] Negative regulation of osteoclastogenesis by ectodomain shedding of receptor activator of NF-kappaB ligand. (2006)
  • Author(s): Hikita, A., I.Yana, H.Wakeyama, M.Nakamura, Y.Kadono, Y.Oshima, K.Nakamura, M.Seiki, S.Tanaka.
  • Journal Title: J Biol Chem 281 Pages: 36846-36855
• [Journal Article] Cell surface collagenolysis requires homodimerization of the membrane-bound collagenase MT1-MMP. (2006)
  • Author(s): Itoh, Y., N.Ito, H.Nagase, R.D.Evans, S.A.Bird, M.Seiki.
  • Journal Title: Mol Biol Cell 17 Pages: 5390-5399
• [Journal Article] MT1-MMP : a potent modifier of pericellular microenvironment. (2006)
  • Author(s): Itoh, Y.M.Seiki.
  • Journal Title: J Cell Physiol 206 Pages: 1-8
• [Journal Article] Type I collagen abrogates the clathrin-mediated internalization of membrane type 1 matrixmetalloproteinase (MT1-MMP) via the MT1-MMP hemopexin domain. (2006)
  • Author(s): Lafleur, M.A., F.A. Mercuri, N.Ruangpanit, M.Seiki, H.Sato, E.W.Thompson.
  • Journal Title: J Biol Chem 281 Pages: 6826-6840
• [Journal Article] Multifunctional roles of MT1-MMP in myofiber formation and morphostatic maintenance of skeletal muscle. (2006)
  • Author(s): Ohtake, Y., H.Tojo, M.Seiki.
  • Journal Title: J Cell Sci 119 Pages: 3822-3832
• [Journal Article] Membrane-type 1 matrix metalloproteinase modulates focal adhesion stability and cell migration. (2006)
  • Author(s): Takino, T., Y.Watanabe, M.Matsui, H.Miyamori, T.Kudo, M.Seiki, H.Sato.
  • Journal Title: Exp Cell Res 312 Pages: 1381-1389
• [Journal Article] Membrane type 1 matrix metalloproteinase(MT1-MMP/MMP-14)cleaves and releases a 22-kDa extracellular matrix metalloproteinase inducer(EMMPRIN)fragment from tumor cells (2006)
  • Author(s): Egawa, N., 他5名
  • Journal Title: J. Biol. Chem 281・49 Pages: 37576-85
• [Journal Article] Negative regulation of osteoclastogenesis by ectodomain shedding of receptor activator of NF-kappaB ligand (2006)
  • Author(s): Hikita, A., 他8名
  • Journal Title: J. Biol. Chem 281・48 Pages: 36846-55
• [Journal Article] Multifunctional roles of MT1-MMP in myofiber formation and morphostatic maintenance of skeletal muscle (2006)
  • Author(s): Ohtake, Y, 他2名
  • Journal Title: J. Cell Science 119・18 Pages: 3822-32
• [Journal Article] Membrane-type 1 matrix metalloproteinase modulates focal adhesion stability and cell migration (2006)
  • Author(s): Takino, T., 他6名
  • Journal Title: Exp. Cell Research 312・8 Pages: 1381-9
• [Journal Article] Type I collagen abrogates the clathrin-mediated internalization of membrane type 1 matrix metalloproteinase(MT1-MMP)via the MT1-MMP hemopexin domain (2006)
  • Author(s): Lafleur, M. A., 他5名
  • Journal Title: J. Biol. Chem 281・10 Pages: 6826-40
• [Journal Article] CD44 bindng through the hemopexin-like domain is critical for its shedding by membrane-type 1 matrix metalloproteinase (2006)
  • Author(s): Suenaga, N 他3名
  • Journal Title: Oncogene 24・5 Pages: 859-868
• [Journal Article] MT1-MMP : a potent modifier of pericellular microenvironment (2006)
  • Author(s): Itoh, Y., Seiki, M.
  • Journal Title: J Cell Physiol 1 Pages: 1-8
• [Journal Article] Palmitoylation at Cys574 is essential for MT1-MMP to promote cell migration. (2005)
  • Author(s): Anilkumar, N., T.Uekita, J.R.Couchman, H.Nagase, M.Seiki, Y.Itoh.
  • Journal Title: Faseb J 19 Pages: 1326-1328
• [Journal Article] Jr.Matrix metalloproteinase expression and function during fin regeneration in zebrafish : analysis of MT1-MMP, MMP2 and TIMP2. (2005)
  • Author(s): Bai, S., R.Thummel, A.R.Godwin, H.Nagase, Y.Itoh, L.Li, R.Evans, J.McDermott, M.Seiki, M.P.Sarras
  • Journal Title: Matrix Biol 24 Pages: 247-260
• [Journal Article] Membrane-type 1 matrix metalloproteinase cytoplasmic tail binding protein-1 (MTCBP-1) acts as an eukaryotic aci-reductone dioxygenase ARD) in the methionine salvage pathway. (2005)
  • Author(s): Hirano, W., I.Gotoh, T.Uekita, M.Seiki.
  • Journal Title: Genes Cells 10 Pages: 565-574
• [Journal Article] Impaired alveolization in mice deficient in membrane-type matrix metalloproteinase 1 (MT1-MMP). (2005)
  • Author(s): Irie, K., K.Komori, M.Seiki, E.Tsuruga, Y.Sakakura, T.Kaku, T.Yajima.
  • Journal Title: Med Mol Morphol 38 Pages: 43-46
  • NAID: 10018374513
• [Journal Article] Membrane-type matrix metalloproteinase-1 (MT1-MMP) is a processing enzyme for human laminin gamma 2 chain. (2005)
  • Author(s): Koshikawa, N., T.Minegishi, A.Sharabi, V.Quaranta, M.Seiki.
  • Journal Title: J Biol Chem 280 Pages: 88-93
• [Journal Article] Competitive disruption of the tumor-promoting function of membrane type 1 matrix metalloproteinase/matrix metalloproteinase-14 in vivo. (2005)
  • Author(s): Nonaka, T., K.Nishibashi, Y.Itoh, I.Yana, M.Seiki.
  • Journal Title: Mol Cancer Ther 4 Pages: 1157-1166
• [Journal Article] CD44 binding through the hemopexin-like domain is critical for its shedding by membrane-type 1 matrix metalloproteinase. (2005)
  • Author(s): Suenaga, N., H.Mori, Y.Itoh, M.Seiki.
  • Journal Title: Oncogene 24 Pages: 859-868
• [Journal Article] Cell surtace collagenolysis requires homodimerization of the membrane-bound collagenase MT1-MMP (2005)
  • Author(s): Itoh, Y, 他5名.
  • Journal Title: Mol Biol Cell 17・12 Pages: 5390-9
• [Journal Article] Membrane-type 1 matrix metalloproteinase cytoplasmic tai1 binding protein-1(MTCBP-1) acts as an eukaryotic aci-reductone dioxygenase (ARD) in the methionine salvage pathway (2005)
  • Author(s): Hirano, W 他3名
  • Journal Title: Gene Cells 10・6 Pages: 565-574
• [Journal Article] Competitive disruption of the tumor-promoting function of membrane type 1 matrix metalloproteinase/matrix metalloproteinase-14 in vivo (2005)
  • Author(s): Nonaka, T. 他4名
  • Journal Title: Mol Lancer Ther 4・8 Pages: 1157-1166
• [Journal Article] Palmitoylation at Cys574 is essential for MT1-MMP to promote cell migration (2005)
  • Author(s): Anikumar, N. 他5名
  • Journal Title: FASEB J 19・10 Pages: 1326-1328
• [Presentation] A Systemic survey of substracts and regulators of MT1-MMP (2009)
  • Author(s): 清木元治
  • Organizer: Six General Meeting of the International Proteolysis Society
  • Place of Presentation: Australia
• [Presentation] 招待講演・膜型マトリックスメタロプロテアーゼによる細胞機能制御 (2007)
  • Author(s): 清木元治
  • Organizer: 日本ヒトプロテオーム機構第5回大会
  • Place of Presentation: 日本科学未来館、東京
• [Presentation] プロテオミクスによるMT1-MMP複合体解析 (2007)
  • Author(s): 江川長靖
  • Organizer: 日本ヒトプロテオーム機構第5回大会
  • Place of Presentation: 日本科学未来館、東京
• [Presentation] 14癌細胞株のコラーゲン内三次元増殖におけるMT1-MMPの依存性とMM1270の効果 (2007)
  • Author(s): 生見尚子、清木元治
  • Organizer: 第16回日本がん転移学会総会
  • Place of Presentation: 富山国際会議場、富山県
• [Presentation] コラーゲン内三次元環境下でのMT1-MMP依存性増殖を指標にした癌細胞株14種の分類 (2007)
  • Author(s): 生見尚子、清木元治
  • Organizer: 第66回 日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜、横浜市
• [Presentation] ラミニンγ2単鎖に特異的に反応するモノクリナール抗体の作製 (2007)
  • Author(s): 越川直彦、清木元治
  • Organizer: 第66回 日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜、横浜市
• [Presentation] MT1-MMPはマクロファージの浸潤においてECM分解とケモタキシンスをそれぞれ促進する (2007)
  • Author(s): 坂本毅治、清木元治
  • Organizer: 第66回 日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜、横浜市
• [Presentation] マクロファージにおいてMT1-MMPは細胞外基質の分解とエネルギー産生を促進する (2007)
  • Author(s): 坂本毅治、清木元治
  • Organizer: 第30回日本分子生物学会年会・第80回日本生化学会大会 合同大会
  • Place of Presentation: パシフィコ横浜、横浜市
• [Presentation] 膜型MMPによる細胞表層のプロテオリシスと癌細胞の悪性形質の制御 (2007)
  • Author(s): 越川直彦、清木元治
  • Organizer: 第30回日本分子生物学会年会・第80回日本生化学会大会 合同大会
  • Place of Presentation: パシフィコ横浜、横浜市
• [Presentation] がんの生物像を規定する微小環境:膜型MMPによる細胞表層のプロテオリシスと癌細胞の悪性形質の獲得 (2006)
  • Author(s): 越川直彦、清木元治
  • Organizer: 第65回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Remarks] ホームページ等
  • URL: http://www.ims.u-tokyo.ac.jp/cancercell/index.html
• [Patent(Industrial Property Rights)] 泌尿器科がんの検査方法及び検査用キット (2010)
  • Inventor(s): 清木元治、越川直彦、執印太郎、鎌田雅之
  • Industrial Property Rights Holder: 東京大学、高知大学
  • Filing Date: 2010-03-09
• [Patent(Industrial Property Rights)] MT1-MMP,iFIH, FIH-1 によるHIF-1 の制御 (2008)
  • Inventor(s): 清木元治、坂本毅治
  • Industrial Property Rights Holder: 東京大学
  • Filing Date: 2008-06-20