Updated on 2026/06/30

写真a

 
SHIBUYA HIROSHI
 
Organization
Office of Communications and DEI Specially Appointed Professor
Title
Specially Appointed Professor
Homepage
http://www.tmd.ac.jp/mri/mri-mcb/index_j.html
External link

Degree

  • (BLANK) ( Osaka University )

Research Interests

  • Cellular Signal Transduction

  • シグナル伝達

Research Areas

  • Life Science / Molecular biology

  • Life Science / Cell biology

Education

  • University of Tsukuba   Master's Program in Environmental Sciences

    - 1983

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    Country： Japan

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  • University of Tsukuba   Second Cluster of College

    - 1983

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Research History

  • Tokyo Medical and Dental University   Medical Research Institute   Professor

    2000

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Professional Memberships

Papers

  • <scp>GSK3β</scp> Regulates a Novel β‐Catenin Degradation Pathway via the <scp>GID</scp> Complex in Wnt Signaling

    Masahiro Shimizu, Hiroshi Shibuya

    Genes to Cells   30 ( 6 )   2025.11

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    Publishing type：Research paper (scientific journal)   Publisher：Wiley  

    ABSTRACT

    The canonical Wnt signaling pathway plays a pivotal role in regulating cell proliferation, differentiation, and tissue homeostasis. These functions are largely regulated through the degradation of β‐Catenin. Under Wnt‐off conditions, β‐Catenin is phosphorylated by the destruction complex, including GSK3β, and subsequently ubiquitinated by the E3 ligase βTrCP, leading to proteasomal degradation. In this study, we identified a regulatory mechanism in which suppression of GSK3β promotes β‐Catenin degradation via the GID complex, a conserved multi‐subunit E3 ubiquitin ligase. GSK3β knockdown increased β‐Catenin ubiquitination and decreased its protein levels in both the cytoplasm and nucleus, independent of βTrCP. This degradation was rescued by knockdown of GID components MAEA and RMND5A, but not by suppression of βTrCP. Furthermore, Wnt stimulation promoted the interaction between GSK3β and the GID E3 ligases, disrupting the association between MAEA and β‐Catenin and thereby stabilizing β‐Catenin. Together, these findings reveal a GSK3β‐dependent mechanism of β‐Catenin regulation mediated by the GID complex.

    DOI： 10.1111/gtc.70068

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  • Rho family small GTPase Rif regulates Wnt5a-Ror1-Dvl2 signaling and promotes lung adenocarcinoma progression

    Michiru Nishita, Koki Kamizaki, Kyoka Hoshi, Kana Aruga, Ikumi Nishikaku, Hiroshi Shibuya, Kunio Matsumoto, Yasuhiro Minami

    Journal of Biological Chemistry   105248 - 105248   2023.9

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    Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

    DOI： 10.1016/j.jbc.2023.105248

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  • ccl19 and ccl21 affect cell movements and differentiation in early Xenopus development Reviewed

    Toshiyasu Goto, Tatsuo Michiue, Hiroshi Shibuya

    Development, Growth &amp; Differentiation   65 ( 3 )   175 - 189   2023.3

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    Publishing type：Research paper (scientific journal)   Publisher：Wiley  

    Abstract

    We characterized Xenopus laevis C‐C motif chemokine ligand 19.L (ccl19.L) and C‐C motif chemokine ligand 21.L (ccl21.L) during early Xenopus embryogenesis. The temporal and spatial expression patterns of ccl19.L and ccl21.L tended to show an inverse correlation, except that the expression level was higher in the dorsal side at the gastrula stage. For example, even at the dorsal sector of the gastrulae, ccl19.L was expressed in the axial region and ccl21.L was expressed in the paraxial region. Dorsal overexpression of ccl19.L and ccl21.L and knockdown of Ccl19.L and Ccl21.L inhibited gastrulation, but their functions were different in cell behaviors during morphogenesis. Observation of Keller sandwich explants revealed that overexpression of both ccl19.L and ccl21.L and knockdown of Ccl21.L inhibited the convergent extension movements, while knockdown of Ccl19.L did not. ccl19.L‐overexpressing explants attracted cells at a distance and ccl21.L‐overexpressing explants attracted neighboring cells. Ventral overexpression of ccl19.L and ccl21.L induced secondary axis‐like structures and chrd.1 expression at the ventral side. Upregulation of chrd.1 was induced by ligand mRNAs through ccr7.S. Knockdown of Ccl19.L and Ccl21.L inhibited gastrulation and downregulated chrd.1 expression at the dorsal side. The collective findings indicate that ccl19.L and ccl21.L might play important roles in morphogenesis and dorsal–ventral patterning during early embryogenesis in Xenopus.

    DOI： 10.1111/dgd.12847

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    Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/dgd.12847

  • maea affects head formation through ß-catenin degradation during early Xenopus laevis development. Reviewed

    Toshiyasu Goto, Hiroshi Shibuya

    Development, growth & differentiation   2022.11

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    Canonical Wnt signalling plays important roles in early embryogenesis, such as axis formation due to its activation and head formation due to its inhibition. ß-catenin protein stability is a key factor in canonical Wnt signalling. Several E3 ubiquitin ligases contribute to ß-catenin degradation through the ubiquitin/proteasome system. We characterised an E3 ubiquitin ligase gene, Xenopus laevis macrophage erythroblast attacher (maea), during early development. maea transcripts were ubiquitously detected in early embryos. The expression levels of the Wnt target genes nodal homolog 3, gene 1 (nodal3.1), and siamois homeodomain 1 (sia1), which were induced by injection with ß-catenin mRNA, were reduced by maea.S mRNA co-injection. maea.S overexpression at the anterior dorsal region enlarged head structures, whereas Maea knockdown interfered with head formation in Xenopus embryos. Maea.S decreased and ubiquitinated ß-catenin protein. ß-catenin-4KRs protein, which mutated the four lysine (K) residues known as ubiquitinated sites to arginine (R) residues, was also ubiquitinated and degraded by Maea.S. These findings suggest that Maea contributes to β-catenin degradation by ubiquitination of unknown lysine residues in early Xenopus development.

    DOI： 10.1111/dgd.12828

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  • WNK1/HSN2 mediates neurite outgrowth and differentiation via a OSR1/GSK3β-LHX8 pathway. International journal

    Masahiro Shimizu, Hiroshi Shibuya

    Scientific reports   12 ( 1 )   15858 - 15858   2022.9

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    With no lysine kinase 1 (WNK1) phosphorylates and activates STE20/SPS1-related proline-alanine-rich protein kinase (SPAK) and oxidative stress responsive kinase 1 (OSR1) to regulate ion homeostasis in the kidney. Mutations in WNK1 result in dysregulation of the WNK1-SPAK/OSR1 pathway and cause pseudohypoaldosteronism type II (PHAII), a form of hypertension. WNK1 is also involved in the autosomal recessive neuropathy, hereditary sensory and autonomic neuropathy type II (HSANII). Mutations in a neural-specific splice variant of WNK1 (HSN2) cause HSANII. However, the mechanisms underlying HSN2 regulation in neurons and effects of HSN2 mutants remain unclear. Here, we found that HSN2 regulated neurite outgrowth through OSR1 activation and glycogen synthase kinase 3β (GSK3β). Moreover, HSN2-OSR1 and HSN2-GSK3β signalling induced expression of LIM homeobox 8 (Lhx8), which is a key regulator of cholinergic neural function. The HSN2-OSR1/GSK3β-LHX8 pathway is therefore important for neurite outgrowth. Consistently, HSN2 mutants reported in HSANII patients suppressed SPAK and OSR1 activation and LHX8 induction. Interestingly, HSN2 mutants also suppressed neurite outgrowth by preventing interaction of between wild-type HSN2 and GSK3β. These results indicate that HSN2 mutants cause dysregulation of neurite outgrowth via GSK3β in the HSN2 and/or WNK1 pathways.

    DOI： 10.1038/s41598-022-20271-y

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  • ccr7 affects both morphogenesis and differentiation during early Xenopus embryogenesis. Reviewed

    Toshiyasu Goto, Tatsuo Michiue, Hiroshi Shibuya

    Development, growth & differentiation   64 ( 5 )   254 - 260   2022.6

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    Chemokines play important roles in early embryogenesis, including morphogenesis and cell differentiation, before the immune system is established. We characterized Xenopus laevis CC-type chemokine receptor 7 S (ccr7.S) to clarify its role during early development. ccr7 transcripts were detected ubiquitously in early embryos. Dorsal overexpression of ccr7.S inhibited gastrulation, and ccr7.S mRNA-injected embryos had short axes and widely opened neural folds. Because the Keller sandwich explants of the injected embryos elongated well, ccr7.S might affect cell migration, but not convergent extension movements. Ventral ccr7.S overexpression induced secondary axes and chrd.1 upregulation in gastrula-stage embryos. Animal cap assays showed increased expression of neural and cement gland marker genes at later stages. Ccr7.S knockdown reduced chrd.1 expression and inhibited gastrulation at the dorsal side. Our findings suggest that ccr7.S plays important roles in morphogenetic movement and cell differentiation.

    DOI： 10.1111/dgd.12790

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  • WNK regulates Wnt signalling and β-Catenin levels by interfering with the interaction between β-Catenin and GID Reviewed International journal

    Atsushi Sato, Masahiro Shimizu, Toshiyasu Goto, Hiroyuki Masuno, Hiroyuki Kagechika, Nobuyuki Tanaka, Hiroshi Shibuya

    Communications Biology   3 ( 1 )   666 - 666   2020.12

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

    <title>Abstract</title>β-Catenin is an important component of the Wnt signalling pathway. As dysregulation or mutation of this pathway causes many diseases, including cancer, the β-Catenin level is carefully regulated by the destruction complex in the Wnt signalling pathway. However, the mechanisms underlying the regulation of β-Catenin ubiquitination and degradation remain unclear. Here, we find that WNK (With No Lysine [K]) kinase is a potential regulator of the Wnt signalling pathway. We show that WNK protects the interaction between β-Catenin and the Glucose-Induced degradation Deficient (GID) complex, which includes an E3 ubiquitin ligase targeting β-Catenin, and that WNK regulates the β-Catenin level. Furthermore, we show that WNK inhibitors induced β-Catenin degradation and that one of these inhibitors suppressed xenograft tumour development in mice. These results suggest that WNK is a previously unrecognized regulator of β-Catenin and a therapeutic target of cancer.

    DOI： 10.1038/s42003-020-01386-2

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    Other Link： http://www.nature.com/articles/s42003-020-01386-2

  • WDR26 is a new partner of Axin1 in the canonical Wnt signaling pathway Reviewed

    Toshiyasu Goto, Junhei Matsuzawa, Shun-ichiro Iemura, Tohru Natsume, Hiroshi Shibuya

    FEBS LETTERS   590 ( 9 )   1291 - 1303   2016.5

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    DOI： 10.1002/1873-3468.12180

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  • Chaperone complex BAG2-HSC70 regulates localization of Caenorhabditis elegans leucine-rich repeat kinase LRK-1 to the Golgi Reviewed

    Takashi Fukuzono, Strahil Iv. Pastuhov, Okinobu Fukushima, Chun Li, Ayuna Hattori, Shun-ichiro Iemura, Tohru Natsume, Hiroshi Shibuya, Hiroshi Hanafusa, Kunihiro Matsumoto, Naoki Hisamoto

    GENES TO CELLS   21 ( 4 )   311 - 324   2016.4

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    DOI： 10.1111/gtc.12338

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  • Selective inhibition of the kinase DYRK1A by targeting its folding process Reviewed

    Isao Kii, Yuto Sumida, Yuto Sumida, Toshiyasu Goto, Rie Sonamoto, Yukiko Okuno, Suguru Yoshida, Tomoe Kato-Sumida, Tomoe Kato-Sumida, Yuka Koike, Yuka Koike, Minako Abe, Yosuke Nonaka, Teikichi Ikura, Nobutoshi Ito, Hiroshi Shibuya, Takamitsu Hosoya, Masatoshi Hagiwara

    Nature Communications   7   2016.4

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    Language：English   Publisher：Nature Publishing Group  

    DOI： 10.1038/ncomms11391

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  • Hipk2 and PP1c cooperate to maintain Dvl protein levels required for Wnt signal transduction. Reviewed

    Shimizu N, Ishitani S, Sato A, Shibuya H, Ishitani T

    Cell reports   8 ( 5 )   1391 - 1404   2014.9

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  • IQGAP1 protein regulates nuclear localization of β-catenin via importin-β5 protein in Wnt signaling. Reviewed

    Goto T, Sato A, Adachi S, Iemura S, Natsume T, Shibuya H

    The Journal of biological chemistry   288 ( 51 )   36351 - 36360   2013.12

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  • IQGAP1 protein regulates nuclear localization of beta-catenin via importin-beta5 protein in Wnt signaling. Reviewed

    Goto Toshiyasu, Sato Atsushi, Adachi Shungo, Iemura Shun-ichiro, Natsume Tohru, Shibuya Hiroshi

    J Biol Chem   288 ( 51 )   36351 - 36360   2013.12

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    In the canonical Wnt signaling pathway, the translocation of beta-catenin is important for the activation of target genes in the nucleus. However, the molecular mechanisms underlying its nuclear localization remain unclear. In the present study, we found IQGAP1 to be a regulator of beta-catenin function via importin-beta5. In Xenopus embryos, depletion of IQGAP1 reduced Wnt-induced nuclear accumulation of beta-catenin and expression of Wnt target genes during early embryogenesis. Depletion of endogenous importin-beta5 associated with IQGAP1 also reduced expression of Wnt target genes and the nuclear localization of IQGAP1 and beta-catenin. Moreover, a small GTPase, Ran1, contributes to the nuclear translocation of beta-catenin and the activation of Wnt target genes. These results suggest that IQGAP1 functions as a regulator of translocation of beta-catenin in the canonical Wnt signaling pathway.

    DOI： 10.1074/jbc.M113.520528

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  • WNK4 is an essential effector of anterior formation in FGF signaling. Reviewed

    Shimizu Masahiro, Goto Toshiyasu, Sato Atsushi, Shibuya Hiroshi

    Genes Cells   18 ( 6 )   442 - 449   2013.6

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    With no lysine (K) (WNK) kinase family is conserved among many species and regulates SPAK/OSR1 and ion cotransporters. WNK is also involved in developmental and cellular processes, but the molecular mechanisms underlying its regulation in these processes remain unknown. In this study, we found that WNK4 is involved in fibroblast growth factor (FGF) signaling during Xenopus development. In Xenopus embryos, depletion of WNK4 by antisense morpholino oligonucleotides (MOs) results in a severe defect in anterior development and impaired expression of endogenous anterior markers. Defects in head formation or expression of anterior marker genes caused by suppression of endogenous WNK4 expression could be rescued by expression of wild-type WNK4, but not mutant WNK4 lacking its kinase activity. It is notable that morphants of Xenopus WNK4 inhibited the expression of anterior marker genes and the target genes induced by FGF signaling. Moreover, knockdown of Wnk4 significantly reduced the phosphorylation level of Osr1 induced by FGF. These results provide the first evidence that FGF signaling regulates WNK4 function required for anterior formation in Xenopus development.

    DOI： 10.1111/gtc.12048

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  • IQGAP1 functions as a modulator of dishevelled nuclear localization in Wnt signaling. Reviewed

    Goto Toshiyasu, Sato Atsushi, Shimizu Masahiro, Adachi Shungo, Satoh Kiyotoshi, Iemura Shun-ichiro, Natsume Tohru, Shibuya Hiroshi

    PLoS One   8 ( 4 )   e60865 - e60865   2013.4

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    DOI： 10.1371/journal.pone.0060865,

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  • Leucine-rich repeat kinase LRRK1 regulates endosomal trafficking of the EGF receptor Reviewed

    Hiroshi Hanafusa, Kouki Ishikawa, Shin Kedashiro, Tsukasa Saigo, Shun-ichiro Iemura, Tohru Natsume, Masayuki Komada, Hiroshi Shibuya, Atsuki Nara, Kunihiro Matsumoto

    NATURE COMMUNICATIONS   2   158   2011.1

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    DOI： 10.1038/ncomms1161

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  • Xenopus furry contributes to release of microRNA gene silencing Reviewed

    Toshiyasu Goto, Akimasa Fukui, Hiroshi Shibuya, Ray Keller, Makoto Asashima

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   107 ( 45 )   19344 - 19349   2010.11

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    DOI： 10.1073/pnas.1008954107

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  • Development of a novel selective inhibitor of the Down syndrome-related kinase Dyrk1A Reviewed

    Ogawa Yasushi, Nonaka Yosuke, Goto Toshiyasu, Ohnishi Eriko, Hiramatsu Toshiyuki, Kii Isao, Yoshida Miyo, Ikura Teikichi, Onogi Hiroshi, Shibuya Hiroshi, Hosoya Takamitsu, Ito Nobutoshi, Hagiwara Masatoshi

    Nature Communications   1   86   2010.10

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  • CHIP-dependent termination of MEKK2 regulates temporal ERK activation required for proper hyperosmotic response Reviewed

    Takeshi Maruyama, Hisae Kadowaki, Noriaki Okamoto, Atsushi Nagai, Isao Naguro, Atsushi Matsuzawa, Hiroshi Shibuya, Keiji Tanaka, Shigeo Murata, Kohsuke Takeda, Hideki Nishitoh, Hidenori Ichijo

    EMBO JOURNAL   29 ( 15 )   2501 - 2514   2010.8

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1038/emboj.2010.141

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    Other Link： http://orcid.org/0000-0002-8359-8399

  • Nemo-like kinase (NLK) expression in osteoblastic cells and suppression of osteoblastic differentiation Reviewed

    Akira Nifuji, Hisashi Ideno, Yoshio Ohyama, Rieko Takanabe, Ryoko Araki, Masumi Abe, Masaki Noda, Hiroshi Shibuya

    EXPERIMENTAL CELL RESEARCH   316 ( 7 )   1127 - 1136   2010.4

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    DOI： 10.1016/j.yexcr.2010.01.023

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  • Nemo-like kinase, an essential effector of anterior formation, functions downstream of p38 mitogen-activated protein kinase. Reviewed

    Ohnishi E, Goto T, Sato A, Kim MS, Iemura S, Ishitani T, Natsume T, Ohnishi J, Shibuya H

    Molecular and cellular biology   30   675 - 683   2010.2

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  • Nemo-like kinase, an essential effector of anterior formation, functions downstream of p38 mitogen-activated protein kinase. Reviewed

    Ohnishi Eriko, Goto Toshiyasu, Sato Atsushi, Kim Mi-Sun, Iemura Shun-Ichiro, Ishitani Tohru, Natsume Tohru, Ohnishi Junji, Shibuya Hiroshi

    Mol Cell Biol   30 ( 3 )   675 - 683   2010.2

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    Nemo-like kinase (NLK) is known to function as a mitogen-activated protein kinase (MAPK)-like kinase. However, the upstream molecules and molecular mechanisms that regulate NLK activity remain unclear. In the present study, we identified p38 MAPK as an upstream kinase and activator of NLK. p38 regulates the function of NLK via phosphorylation, and this modification can be abrogated by depletion of endogenous p38. In Xenopus laevis embryos, depletion of either p38beta or NLK by antisense morpholino oligonucleotides results in a severe defect in anterior development and impaired expression of endogenous anterior markers. It is notable that morphants of Xenopus p38alpha, another isoform of the p38 MAPK family, exhibited no obvious defects in anterior development. Defects in head formation or in the expression of anterior marker genes caused by suppression of endogenous p38beta expression could be rescued by expression of wild-type NLK but not by expression of mutant NLK lacking the p38beta phosphorylation site. In contrast, defects in head formation or in the expression of anterior marker genes caused by suppression of endogenous NLK expression could not be rescued by expression of p

    DOI： 10.1128/MCB.00576-09

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  • TMEPAI, a Transmembrane TGF-β-Inducible Protein, Sequesters Smad Proteins from Active Participation in TGF-β Signaling

    Watanabe Yukihide, Itoh Susumu, Goto Toshiyasu, Ohnishi Eriko, Inamitsu Masako, Itoh Fumiko, Satoh Kiyotoshi, Wiercinska Eliza, Yang Weiwen, Shi Liang, Tanaka Aya, Nakano Naoko, Mieke Mommaas A., Shibuya Hiroshi, Dijke Peter ten, Kato Mitsuyasu

    Molecular cell   37 ( 1 )   123 - 134   2010.1

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    Language：English   Publisher：Elsevier (Cell press)  

    DOI： 10.1016/j.molcel.2009.10.028

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  • Caenorhabditis elegans WNK-STE20 pathway regulates tube formation by modulating ClC channel activity Reviewed

    Naoki Hisamoto, Tetsuo Moriguchi, Seiichi Urushiyama, Shohei Mitani, Hiroshi Shibuya, Kunihiro Matsumoto

    EMBO REPORTS   9 ( 1 )   70 - 75   2008.1

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    DOI： 10.1038/sj.embor.7401128

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  • A histone lysine methyltransferase activated by non- canonical Wnt signalling suppresses PPAR-gamma transactivation Reviewed

    Ichiro Takada, Masatomo Mihara, Miyuki Suzawa, Fumiaki Ohtake, Shinji Kobayashi, Mamoru Igarashi, Min-Young Youn, Ken-ichi Takeyama, Takashi Nakamura, Yoshihiro Mezaki, Shinichiro Takezawa, Yoshiko Yogiashi, Hirochika Kitagawa, Gen Yamada, Shinji Takada, Yasuhiro Minami, Hiroshi Shibuya, Kunihiro Matsumoto, Shigeaki Kato

    NATURE CELL BIOLOGY   9 ( 11 )   1273 - U118   2007.11

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    DOI： 10.1038/ncb1647

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  • Nemo-like kinase-myocyte enhancer factor 2A signaling regulates anterior formation in xenopus development Reviewed

    Kiyotoshi Satoh, Junji Ohnishi, Atsushi Sato, Michio Takeyama, Shun-Ichiro Iemura, Tohru Natsume, Hiroshi Shibuya

    MOLECULAR AND CELLULAR BIOLOGY   27 ( 21 )   7623 - 7630   2007.11

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    DOI： 10.1128/MCB.01481-07

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  • The adaptor-like protein ROG-1 is required for activation of the Ras-MAP kinase pathway and meiotic cell cycle progression in Caenorhabditis elegans Reviewed

    Yosuke Matsubara, Ichiro Kawasaki, Seiichi Urushiyama, Tomoharu Yasuda, Masaki Shirakata, Yuichi Iino, Hiroshi Shibuya, Yuji Yamanashi

    GENES TO CELLS   12 ( 3 )   407 - 420   2007.3

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    DOI： 10.1111/j.1365-2443.2007.01061.x

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  • Role of a BCL9-related beta-catenin-binding protein, B9L, in tumorigenesis induced by aberrant activation of Wnt signaling Reviewed

    S Adachi, T Jigami, T Yasui, T Nakano, S Ohwada, Y Omori, S Sugano, B Ohkawara, H Shibuya, T Nakamura, T Akiyama

    CANCER RESEARCH   64 ( 23 )   8496 - 8501   2004.12

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  • Manipulation of alternative splicing by a newly developed inhibitor of Clks Reviewed

    M Muraki, B Ohkawara, T Hosoya, H Onogi, J Koizumi, T Koizumi, K Sumi, Y Jun-ichiro, MV Murray, H Kimura, K Furuichi, H Shibuya, AR Krainer, M Suzuki, M Hagiwara

    JOURNAL OF BIOLOGICAL CHEMISTRY   279 ( 23 )   24246 - 24254   2004.6

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    DOI： 10.1074/jbc.M314298200

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  • The receptor tyrosine kinase Ror2 is involved in non-canonical Wnt5a/JNK signalling pathway. International journal

    Isao Oishi, Hiroaki Suzuki, Nobuyuki Onishi, Ritsuko Takada, Shuichi Kani, Bisei Ohkawara, Ikue Koshida, Kentaro Suzuki, General Yamada, Georg C Schwabe, Stefan Mundlos, Hiroshi Shibuya, Shinji Takada, Yasuhiro Minami

    Genes to cells : devoted to molecular & cellular mechanisms   8 ( 7 )   645 - 54   2003.7

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    BACKGROUND: Ror2 is an orphan receptor, belonging to the Ror family of receptor tyrosine kinases. Although Ror2 has been shown to play crucial roles in developmental morphogenesis, the precise signalling events that Ror2 mediates remain elusive. Since Ror2 possesses an extracellular cysteine-rich domain (CRD) that resembles the Wnt-binding sites of the Frizzled (Fz) proteins, it is conceivable that Ror2 interacts with members of the Wnt family. RESULTS: Both Ror2-/- and Wnt5a-/- mice exhibit dwarfism, facial abnormalities, short limbs and tails, dysplasia of lungs and genitals, and ventricular septal defects. In vitro binding assay revealed that Wnt5a binds to the CRD of Ror2. Furthermore, Ror2 associates via its CRD with rFz2, a putative receptor for Wnt5a. Interestingly, Wnt5a and Ror2 activate the non-canonical Wnt pathway, as assessed by activation of JNK in cultured cells and inhibition of convergent extension movements in Xenopus. CONCLUSIONS: Our findings indicate that Wnt5a and Ror2 interact physically and functionally. Ror2 may thus act as a receptor for Wnt5a to activate non-canonical Wnt signalling.

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  • Inhibition of BMP2-induced, TAK1 kinase-mediated neurite outgrowth by Smad6 and Smad7. International journal

    M Yanagisawa, K Nakashima, K Takeda, W Ochiai, T Takizawa, M Ueno, M Takizawa, H Shibuya, T Taga

    Genes to cells : devoted to molecular & cellular mechanisms   6 ( 12 )   1091 - 9   2001.12

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    BACKGROUND: BMP2 is known to play a wide variety of roles, including some in the development of the nervous system. This cytokine has been reported to induce neurite outgrowth in rat pheochromocytoma PC12 cells via the activation of a p38 MAP kinase, although its regulatory mechanism remains largely to be elucidated. RESULTS: BMP2-induced neurite outgrowth in PC12 cells was inhibited by the introduction of a kinase-negative form of a MAP kinase kinase kinase, TAK1, an upstream regulatory kinase for p38 kinase. Following BMP2 stimulation, the expression of Smad6 and Smad7, inhibitory Smad species that are known to inhibit the BMP2-restricted Smad species, Smad1, Smad5 and Smad8, was up-regulated. Unexpectedly, over-expression of either Smad6 or Smad7 in PC12 cells repressed the BMP2-induced neurite outgrowth and severely impeded the p38 kinase pathway. Both of these inhibitory Smads were found to interact physically with TAK1-binding protein, a molecule required for TAK1 activation. CONCLUSIONS: This study demonstrates that BMP2-induced neurite outgrowth in PC12 cells involves activation of the TAK1-p38 kinase pathway which is inhibited by Smad6 and Smad7.

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  • Dlxin-1, a novel protein that binds D1x5 and regulates its transcriptional function Reviewed

    Y Masuda, A Sasaki, H Shibuya, N Ueno, K Ikeda, K Watanabe

    JOURNAL OF BIOLOGICAL CHEMISTRY   276 ( 7 )   5331 - 5338   2001.2

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  • Regulation of the activity of the transcription factor Runx2 by two homeobox proteins, Msx2 and Dlx5 Reviewed

    K. Shirakabe, K. Terasawa, K. Miyama, H. Shibuya, E. Nishida

    Genes to Cells   6 ( 10 )   851 - 856   2001

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  • BMP2-induced apoptosis is mediated by activation of the TAK1-p38 kinase pathway that is negatively regulated by Smad6. Reviewed

    Kimura N, Matsuo R, Shibuya H, Nakashima K, Taga T

    The Journal of biological chemistry   275 ( 23 )   17647 - 17652   2000.6

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  • Involvement of the p38 mitogen-activated protein kinase pathway in transforming growth factor-beta-induced gene expression. Reviewed International journal

    H Hanafusa, J Ninomiya-Tsuji, N Masuyama, M Nishita, J Fujisawa, H Shibuya, K Matsumoto, E Nishida

    The Journal of biological chemistry   274 ( 38 )   27161 - 7   1999.9

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    Transforming growth factor-beta (TGF-beta)-activated kinase 1 (TAK1), a member of the mitogen-activated protein kinase kinase kinase family, is suggested to be involved in TGF-beta-induced gene expression, but the signaling mechanism from TAK1 to the nucleus remains largely undefined. We have found that p38 mitogen-activated protein kinase, and its direct activator MKK6 are rapidly activated in response to TGF-beta. Expression of dominant negative MKK6 or dominant negative TAK1 inhibited the TGF-beta-induced transcriptional activation as well as the p38 activation. Constitutive activation of the p38 pathway in the absence of TGF-beta induced the transcriptional activation, which was enhanced synergistically by coexpression of Smad2 and Smad4 and was inhibited by expression of the C-terminal truncated, dominant negative Smad4. Furthermore, we have found that activating transcription factor-2 (ATF-2), which is known as a nuclear target of p38, becomes phosphorylated in the N-terminal activation domain in response to TGF-beta, that ATF-2 forms a complex with Smad4, and that the complex formation is enhanced by TGF-beta. In addition, expression of a nonphosphorylatable form of ATF-2 inhibited the TGF-beta-induced transcriptional activation. These results show that the p38 pathway is activated by TGF-beta and is involved in the TGF-beta-induced transcriptional activation by regulating the Smad-mediated pathway.

    DOI： 10.1074/jbc.274.38.27161

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  • Constitutively active BMP type I receptors transduce BMP-2 signals without the ligand in C2C12 myoblasts Reviewed

    S Akiyama, T Katagiri, M Namiki, N Yamaji, N Yamamoto, K Miyama, H Shibuya, N Ueno, JM Wozney, T Suda

    EXPERIMENTAL CELL RESEARCH   235 ( 2 )   362 - 369   1997.9

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    DOI： 10.1006/excr.1997.3680

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    Other Link： http://orcid.org/0000-0002-8375-2317

  • C-FOS GENE INDUCTION BY INTERLEUKIN-2 - IDENTIFICATION OF THE CRITICAL CYTOPLASMIC REGIONS WITHIN THE INTERLEUKIN-2 RECEPTOR-BETA CHAIN Reviewed

    M HATAKEYAMA, A KAWAHARA, H MORI, H SHIBUYA, T TANIGUCHI

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   89 ( 6 )   2022 - 2026   1992.3

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  • Regulation of cytokine gene expression: gene activation in type I IFN and IL-2 systems. Reviewed

    T. Taniguchi, T. Fujita, G. Yamada, M. Hatakeyama, E. Ishizaka, M. Miyamoto, M. Maruyama, H. Shibuya

    Princess Takamatsu symposia   19   279 - 286   1988

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  • Regulation of the interleukin-2 system and T cell neoplasm. Reviewed

    T. Taniguchi, G. Yamada, H. Shibuya, M. Maruyama, H. Harada, M. Hatakeyama, T. Fujita

    IARC scientific publications   ( 92 )   181 - 184   1988

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  • INTERLEUKIN-2 AND ITS RECEPTOR - STRUCTURE AND FUNCTIONAL EXPRESSION OF THE GENES Invited Reviewed

    T TANIGUCHI, T FUJITA, M HATAKEYAMA, H MORI, H MATSUI, T SATO, J HAMURO, S MINAMOTO, G YAMADA, H SHIBUYA

    COLD SPRING HARBOR SYMPOSIA ON QUANTITATIVE BIOLOGY   51 ( 1 )   577 - 586   1986

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MISC

  • DNA demethylation in hormone-induced transcriptional derepression (Retracted article. See vol. 486, pg. 280, 2012)

    Mi-Sun Kim, Takeshi Kondo, Ichiro Takada, Min-Young Youn, Yoko Yamamoto, Sayuri Takahashi, Takahiro Matsumoto, Sally Fujiyama, Yuko Shirode, Ikuko Yamaoka, Hirochika Kitagawa, Ken-Ichi Takeyama, Hiroshi Shibuya, Fumiaki Ohtake, Shigeaki Kato

    NATURE   461 ( 7266 )   1007 - 1012   2009.10

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  • DNA Demethylation for Hormone-Induced Transcriptional Derepression

    M. Kim, F. Ohtake, I. Takada, K. Takeyama, H. Shibuya, S. Kato

    JOURNAL OF BONE AND MINERAL RESEARCH   23   S52 - S52   2008.9

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  • Molecular pathogenesis of pseudohypoaldosteronism type II: Generation and analysis of a Wnk4(D561A/+) knockin mouse model

    Sung-Sen Yang, Tetsuji Morimoto, Tatemitsu Rai, Motoko Chiga, Eisei Sohara, Mayuko Ohno, Keiko Uchida, Shih-Hua Lin, Tetsuo Moriguchi, Hiroshi Shibuya, Yoshiaki Kondo, Sei Sasaki, Shinichi Uchida

    CELL METABOLISM   5 ( 5 )   331 - 344   2007.5

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  • NARF, an nemo-like kinase (NLK)-associated ring finger protein regulates the ubiquitylation and degradation of T cell factor/lymphoid enhancer factor (TCF/LEF).

    YAMADA Misato, YAMADA Misato, OHNISHI Junji, OHNISHI Junji, OHKAWARA Bisei, OHKAWARA Bisei, IEMURA Shunichiro, SATOH Kiyotoshi, SATOH Kiyotoshi, HYODO‐MIURA Junko, KAWACHI Kaoru, KAWACHI Kaoru, NATSUME Tohru, SHIBUYA Hiroshi, SHIBUYA Hiroshi

    J Biol Chem.   281 ( 30 )   20749 - 20760   2006

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  • WNK1 regulates phosphorylation of cation-chloride-coupled cotransporters via the STE20-related kinases, SPAK and OSR1.

    MORIGUCHI Tetsuo, MORIGUCHI Tetsuo, URUSHIYAMA Seiichi, HISAMOTO Naoki, IEMURA Shun‐ichiro, UCHIDA Shinichi, NATSUME Tohru, MATSUMOTO Kunihiro, SHIBUYA Hiroshi, SHIBUYA Hiroshi

    JOURNAL OF BIOLOGICAL CHEMISTRY   280 ( 52 )   42685 - 42693   2005

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  • Role of the TAK1-NLK-STAT3 pathway in TGF-beta-mediated mesoderm induction

    B Ohkawara, K Shiratake, J Hyodo-Miura, R Matsuo, N Ueno, K Matsumoto, H Shibuya

    GENES & DEVELOPMENT   18 ( 4 )   381 - 386   2004.2

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  • Manipulation of alternative splicing by a novel inhibitor of Clks

    M Muraki, B Ohkawara, T Hosoya, H Onogi, J Koizumi, T Koizumi, K Sumi, J Yomoda, MV Murray, H Kimura, K Furuichi, H Shibuya, AR Krainer, M Suzuki, M Hagiwara

    JOURNAL OF PHARMACOLOGICAL SCIENCES   94   244P - 244P   2004

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  • Role of the TAB2-related protein TAB3 in IL-1 and TNF signaling

    T Ishitani, G Takaesu, J Ninomiya-Tsuji, H Shibuya, RB Gaynor, K Matsumoto

    EMBO JOURNAL   22 ( 23 )   6277 - 6288   2003.12

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  • Negative regulation of Wnt signalling by HMG2L1, a novel NLK-binding protein

    M Yamada, B Ohkawara, N Ichimura, J Hyodo-Miura, S Urushiyama, K Shirakabe, H Shibuya

    GENES TO CELLS   8 ( 8 )   677 - 684   2003.8

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  • Cytokines suppress adipogenesis and PPAR-function through the TAK1/TAB1/NIK cascade

    M Suzawa, Takada, I, J Yanagisawa, F Ohtake, S Ogawa, T Yamauchi, T Kadowaki, Y Takeuchi, H Shibuya, Y Gotoh, K Matsumoto, S Kato

    NATURE CELL BIOLOGY   5 ( 3 )   224 - 230   2003.3

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  • The TAK1-NLK mitogen-activated protein kinase cascade functions in the Wnt-5a/Ca2+ pathway to antagonize Wnt/beta-catenin signaling

    T Ishitani, S Kishida, J Hyodo-Miura, N Ueno, J Yasuda, M Waterman, H Shibuya, RT Moon, J Ninomiya-Tsuji, K Matsumoto

    MOLECULAR AND CELLULAR BIOLOGY   23 ( 1 )   131 - 139   2003.1

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  • Targeted disruption of the Tab1 gene causes embryonic lethality and defects in cardiovascular and lung morphogenesis

    Y Komatsu, H Shibuya, N Takeda, J Ninomiya-Tsuji, T Yasui, K Miyado, T Sekimoto, N Ueno, K Matsumoto, G Yamada

    MECHANISMS OF DEVELOPMENT   119 ( 2 )   239 - 249   2002.12

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  • BIP, a BRAM-interacting protein involved in TGF-beta signalling, regulates body length in Caenorhabditis elegans

    K Sugawara, K Morita, N Ueno, H Shibuya

    GENES TO CELLS   6 ( 7 )   599 - 606   2001.7

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  • A DAF-1-binding protein BRA-1 is a negative regulator of DAF-7 TGF-beta signaling

    K Morita, M Shimizu, H Shibuya, N Ueno

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   98 ( 11 )   6284 - 6288   2001.5

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  • The TGF-beta family member derriere is involved in regulation of the establishment of left-right asymmetry

    H Hanafusa, N Masuyama, M Kusakabe, H Shibuya, E Nishida

    EMBO REPORTS   1 ( 1 )   32 - 39   2000.7

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  • Inhibition of Wnt signaling by ICAT, a novel beta-catenin-interacting protein

    K Tago, T Nakamura, M Nishita, J Hyodo, S Nagai, Y Murata, S Adachi, S Ohwada, Y Morishita, H Shibuya, T Akiyama

    GENES & DEVELOPMENT   14 ( 14 )   1741 - 1749   2000.7

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  • Direct physical interaction among Lef/Tcf, B-catenin and Smad4 transcription factors in formation of Spemann's Organizer

    MK Hashimoto, M Nishita, S Ogata, MN Laurent, N Ueno, H Shibuya, KWY Cho

    DEVELOPMENTAL BIOLOGY   222 ( 1 )   271 - 271   2000.6

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  • TAK1 participates in c-Jun N-terminal kinase signaling during Drosophila development

    Y Takatsu, M Nakamura, M Stapleton, MC Danos, K Matsumoto, MB O'Connor, H Shibuya, N Ueno

    MOLECULAR AND CELLULAR BIOLOGY   20 ( 9 )   3015 - 3026   2000.5

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  • TAB2, a novel adaptor protein, mediates activation of TAK1 MAPKKK by linking TAK1 to TRAF6 in the IL-1 signal transduction pathway

    G Takaesu, S Kishida, A Hiyama, K Yamaguchi, H Shibuya, K Irie, J Ninomiya-Tsuji, K Matsumoto

    MOLECULAR CELL   5 ( 4 )   649 - 658   2000.4

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  • Wntシグナル伝達系を制御するTAK1-NLK MAPキナーゼカスケード

    石谷太, 辻順, 渋谷浩司, 久本直毅, 松本邦弘

    日本分子生物学会年会プログラム・講演要旨集   23rd   2000

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  • TGF beta/BMP suppresses PPAR gamma function though TAK1/TAB1 mediated signaling pathway.

    M Suzawa, J Yanagisawa, Y Takeuchi, Y Kodera, K Takeyama, H Shibuya, Y Goto, S Kato

    JOURNAL OF BONE AND MINERAL RESEARCH   14   S212 - S212   1999.9

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  • Identification of a factor that cooperates with Wnt-signaling to regulate the homeobox gene Xtwin.

    MK Hashimoto, M Nishita, M Laurent, S Ogata, N Ueno, H Shibuya, KW Cho

    DEVELOPMENTAL BIOLOGY   210 ( 1 )   220 - 220   1999.6

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  • A BMP-inducible gene, D1x5, regulates osteoblast differentiation and mesoderm induction

    K Miyama, G Yamada, TS Yamamoto, C Takagi, K Miyado, M Sakai, N Ueno, H Shibuya

    DEVELOPMENTAL BIOLOGY   208 ( 1 )   123 - 133   1999.4

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  • Identification of two Smad4 proteins in Xenopus - Their common and distinct properties

    N Masuyama, H Hanafusa, M Kusakabe, H Shibuya, E Nishida

    JOURNAL OF BIOLOGICAL CHEMISTRY   274 ( 17 )   12163 - 12170   1999.4

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  • Negative regulation of Wingless signaling by D-axin, a Drosophila homolog of axin

    F Hamada, Y Tomoyasu, Y Takatsu, M Nakamura, S Nagai, A Suzuki, F Fujita, H Shibuya, K Toyoshima, N Ueno, T Akiyama

    SCIENCE   283 ( 5408 )   1739 - 1742   1999.3

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  • Involvement of the p38 MAP kinase pathway in TGF-β-induced gene expression.

    J. Biol. Chem.   274   27161   1999

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  • Wntシグナル伝達系を制御するMAPキナーゼ様カスケード

    石谷太, 辻順, 永井真一, 西田満, MENEGHINI M, BOWERMAN B, 渋谷浩司, 久本直毅, 松本邦弘

    日本分子生物学会年会プログラム・講演要旨集   22nd   1999

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  • Negative regulation of the Wingless signaling by Cougar, a Drosophila homologue of the Axin family of proteins

    HAMADA Fumihiko, TOMOYASU Yoshinori, TAKATSU Yoshihiro, NAKAMURA Makoto, NAGAI Shinichi, FUJITA Fumitaka, SHIBUYA Hiroshi, TOYOSHIMA Kumao, UENO Naoto, AKIYAMA Tetsu

    21   534 - 534   1998.12

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    CiNii Books

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  • Dlxin-1 : a novel Dlx5-binding protein

    MASUDA Yoshiko, SHIBUYA Hiroshi, UENO Naoto, IKEDA Kyoji, WTANABE Ken

    21   627 - 627   1998.12

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  • BRAM1 inhibits Smad2-mediated signaling pathway

    NISHITA M., NAGAI S., UENO N., SHIBUYA H.

    21   532 - 532   1998.12

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  • Identification and functional analysis of Xenopus Smad4α and Smad4β

    MASUYAMA Norihisa, HANAFUSA Hiroshi, KUSAKABE Morioh, SHIBUYA Hiroshi, NISHIDA Eisuke

    21   562 - 562   1998.12

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  • Role of TAK1 and TAB1 in BMP signaling in early Xenopus development

    H Shibuya, H Iwata, N Masuyama, Y Gotoh, K Yamaguchi, K Irie, K Matsumoto, E Nishida, N Ueno

    EMBO JOURNAL   17 ( 4 )   1019 - 1028   1998.2

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  • 線虫C.elegansにおいて,DAF-1レセプターに結合する分子,CeBRAM-1は,DAF-7 TGF-βシグナル伝達経路において抑制因子として働く

    渋谷浩司, 森田清和, 清水美穂, 上野直人

    日本分子生物学会年会プログラム・講演要旨集   21st   1998

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  • TAK1 mediates the ceramide signaling to stress-activated protein kinase c-Jun N-terminal kinase

    K Shirakabe, K Yamaguchi, H Shibuya, K Irie, S Matsuda, T Moriguchi, Y Gotoh, K Matsumoto, E Nishida

    JOURNAL OF BIOLOGICAL CHEMISTRY   272 ( 13 )   8141 - 8144   1997.3

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  • TGF-beta signaling

    J. Ninomiya-Tsuji, K. Matsumoto, H. Shibuya

    Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme   42 ( 10 )   1517 - 1524   1997

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  • TGF-βシグナルに関わる新規伝達因子TAK1, TAB1のアフリカツメガエルによる解析

    岩田 博司, 増山 典久, 後藤 由季子, 西田 栄介, 山口 京子, 入江 賢児, 松本 邦弘, 上野 直人, 澁谷 浩司

    日本分子生物学会年会プログラム・講演要旨集   19   673 - 673   1996.8

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  • Constitutively active BMP type I receptor transduces its signals without any ligands in C2C12 myoblasts.

    S Akiyama, T Katagiri, M Namiki, M Inada, Y Miyama, H Shibuya, N Ueno, N Yamaji, JM Wozney, T Suda

    JOURNAL OF BONE AND MINERAL RESEARCH   11   24 - 24   1996.8

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  • A novel kinase cascade mediated by mitogen-activated protein kinase kinase 6 and MKK3

    T Moriguchi, N Kuroyanagi, K Yamaguchi, Y Gotoh, K Irie, T Kano, K Shirakabe, Y Muro, H Shibuya, K Matsumoto, E Nishida, M Hagiwara

    JOURNAL OF BIOLOGICAL CHEMISTRY   271 ( 23 )   13675 - 13679   1996.6

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  • TAB1: An activator of the TAK1 MAPKKK in TGF-beta signal transduction

    H Shibuya, K Yamaguchi, K Shirakabe, A Tonegawa, Y Gotoh, N Ueno, K Irie, E Nishida, K Matsumoto

    SCIENCE   272 ( 5265 )   1179 - 1182   1996.5

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  • IDENTIFICATION OF A MEMBER OF THE MAPKKK FAMILY AS A POTENTIAL MEDIATOR OF TGF-BETA SIGNAL-TRANSDUCTION

    K YAMAGUCHI, T SHIRAKABE, H SHIBUYA, K IRIE, OISHI, I, N UENO, T TANIGUCHI, E NISHIDA, K MATSUMOTO

    SCIENCE   270 ( 5244 )   2008 - 2011   1995.12

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  • FUNCTIONAL DISSECTION OF P56(LCK), A PROTEIN-TYROSINE KINASE WHICH MEDIATES INTERLEUKIN-2-INDUCED ACTIVATION OF THE C-FOS GENE

    H SHIBUYA, K KOHU, K YAMADA, EL BARSOUMIAN, RM PERLMUTTER, T TANIGUCHI

    MOLECULAR AND CELLULAR BIOLOGY   14 ( 9 )   5812 - 5819   1994.9

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  • IL-2 RECEPTOR AND ITS TARGET GENES IN THE HEMATOPOIETIC-CELL CYCLE

    T TANIGUCHI, Y MINAMI, H SHIBUYA, T KONO, N KOBAYASHI, M YONEYAMA, A KAWAHARA, K YAMADA, S MINAMOTO, M HATAKEYAMA, RM PERLMUTTER

    JOURNAL OF CELLULAR BIOCHEMISTRY   53 - 53   1993.1

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  • IL-2 AND EGF RECEPTORS STIMULATE THE HEMATOPOIETIC-CELL CYCLE VIA DIFFERENT SIGNALING PATHWAYS - DEMONSTRATION OF A NOVEL ROLE FOR C-MYC

    H SHIBUYA, M YONEYAMA, J NINOMIYATSUJI, K MATSUMOTO, T TANIGUCHI

    CELL   70 ( 1 )   57 - 67   1992.7

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  • NEW HUMAN GENE ENCODING A POSITIVE MODULATOR OF HIV TAT-MEDIATED TRANSACTIVATION

    H SHIBUYA, K IRIE, J NINOMIYATSUJI, M GOEBL, T TANIGUCHI, K MATSUMOTO

    NATURE   357 ( 6380 )   700 - 702   1992.6

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  • THE HUMAN INTERLEUKIN-2 RECEPTOR BETA-CHAIN GENE - GENOMIC ORGANIZATION, PROMOTER ANALYSIS AND CHROMOSOMAL ASSIGNMENT

    H SHIBUYA, M YONEYAMA, Y NAKAMURA, H HARADA, M HATAKEYAMA, S MINAMOTO, T KONO, T DOI, R WHITE, T TANIGUCHI

    NUCLEIC ACIDS RESEARCH   18 ( 13 )   3697 - 3703   1990.7

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  • IDENTIFICATION OF MULTIPLE CIS-ELEMENTS AND TRANS-ACTING FACTORS INVOLVED IN THE INDUCED EXPRESSION OF HUMAN IL-2 GENE

    H SHIBUYA, T TANIGUCHI

    NUCLEIC ACIDS RESEARCH   17 ( 22 )   9173 - 9184   1989.11

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  • Involvement of a common transcription factor in the regulated expression of IL-2 and IL-2 receptor genes

    H. Shibuya, M. Yoneyama, T. Taniguchi

    INTERNATIONAL IMMUNOLOGY   1 ( 1 )   43 - 49   1989

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  • INTERFERON-BETA GENE-REGULATION - TANDEMLY REPEATED SEQUENCES OF A SYNTHETIC 6-BP OLIGOMER FUNCTION AS A VIRUS-INDUCIBLE ENHANCER

    T FUJITA, H SHIBUYA, H HOTTA, K YAMANISHI, T TANIGUCHI

    CELL   49 ( 3 )   357 - 367   1987.5

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  • EVIDENCE FOR ABERRANT ACTIVATION OF THE INTERLEUKIN-2 AUTOCRINE LOOP BY HTLV-1-ENCODED P40X AND T3/TI COMPLEX TRIGGERING

    M MARUYAMA, H SHIBUYA, H HARADA, M HATAKEYAMA, M SEIKI, T FUJITA, J INOUE, M YOSHIDA, T TANIGUCHI

    CELL   48 ( 2 )   343 - 350   1987.1

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  • REGULATION OF HUMAN INTERLEUKIN-2 GENE - FUNCTIONAL DNA-SEQUENCES IN THE 5' FLANKING REGION FOR THE GENE-EXPRESSION IN ACTIVATED LYMPHOCYTES-T

    T FUJITA, H SHIBUYA, T OHASHI, K YAMANISHI, T TANIGUCHI

    CELL   46 ( 3 )   401 - 407   1986.8

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  • THE UNIT SEQUENCE WHICH FUNCTIONS AS VIRUS-INDUCIBLE ENHANCER FOR THE HUMAN INTERFERON-BETA GENE-EXPRESSION

    T FUJITA, H SHIBUYA, H HOTTA, T TANIGUCHI

    JOURNAL OF CELLULAR BIOCHEMISTRY   116 - 116   1986

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Awards

  • 日本生化学会奨励賞

    1998  

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Research Projects

  • Regulation of neural differentiation in Wnt signaling by WNK.

    Grant number：21K06165  2021.4 - 2024.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

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    Grant amount：\4160000 （ Direct Cost: \3200000 、 Indirect Cost：\960000 ）

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  • Regulation of neural differentiation in Wnt signaling by WNK.

    Grant number：18K06208  2018.4 - 2021.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Shibuya Hiroshi

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    Grant amount：\4420000 （ Direct Cost: \3400000 、 Indirect Cost：\1020000 ）

    In order to elucidate the function of WNK in the nervous system, we proceeded with the analysis of the Wnt signaling mechanism by WNK, and it was shown that WNK binds to MAEA, which is an E3 ligase, and WNK inhibits the binding between MAEA and β-catenin. It was clarified that the decomposition by the decomposition complex GID was suppressed. Furthermore, when the effect of the WNK inhibitor on the Wnt signal was investigated, it induced ubiquitination and degradation of β-catenin, suppressed the expression of the Wnt target gene, and the WNK inhibitor was less toxic and degraded β-catenin. It was clarified that it efficiently suppresses the formation of colorectal cancer.

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  • Characterization of WNK signaling in development

    Grant number：23390064  2011.4 - 2014.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    HIROSHI Shibuya, SATO Atsushi, GOTO Toshiyasu

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    Grant amount：\19760000 （ Direct Cost: \15200000 、 Indirect Cost：\4560000 ）

    WNK kinase family is conserved among many species and regulates SPAK/OSR1 and ion co-transporters. Some mutations in human WNK1 or WNK4 are associated with Pseudohypoaldosteronism type II, a form of hypertension. Here, we identify a new target gene in WNK signaling, Arrowhead and Lhx8, which is a mammalian homologue of Drosophila Arrowhead. In Drosophila, WNK was shown to genetically interact with Arrowhead. In Wnk1 knockout mice, levels of Lhx8 expression were reduced. Ectopic expression of WNK1, WNK4 or Osr1 in mammalian cells induced the expression of the Lhx8. Moreover, neural specification was inhibited by the knockdown of both Wnk1 and Wnk4 or Lhx8. Drosophila WNK mutant caused defects in axon guidance during embryogenesis. These results suggest that WNK signaling is involved in the morphological and neural development via Lhx8/Arrowhead.

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  • Quantitation analysis of pathway network analysis

    Grant number：17017042  2005 - 2009

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research on Priority Areas

    NATSUME Tohru, IEMURA Shun-ichiro, NAKAYAMA hiroshi, SHIBUYA Kohji

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    Grant amount：\74000000 （ Direct Cost: \74000000 ）

    Cellular signaling comprises numerous numbers of proteins, which interact each other, Forming protein interaction network. To understand networks systematic andcomprehensively, we developed proteomic analytical platform to quantify proteininteractions. By the system, we found several novel signaling pathways.

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  • Regulation of DECODE system in Development

    Grant number：17054013  2005 - 2009

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research on Priority Areas

    SHIBUYA Hiroshi, OHNISHI Junji, SATOH Kiyotoshi, MORIGUCHI Tetsuo, KIM Misun

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    Grant amount：\99200000 （ Direct Cost: \99200000 ）

    We focus on the signal transduction regulating the mechanisms of morphogenesis and organogenesis in development. To explore potential regulators of NLK function, we identified a MAPK, ubiquitin ligase and transcriptional factors as candidate proteins that physically interact with NLK. We finally provided the evidence that these factors specifically regulates NLK function required for the anterior formation in Xenopus development.

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  • Regulation of molecular interaction between TGF-β and Wnt signalings

    Grant number：15390101  2003 - 2004

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    SHIBUYA Hiroshi, URUSHIYAMA Seiichi, SHIRAKABE Kyoko

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    Grant amount：\13400000 （ Direct Cost: \13400000 ）

    TGF-β signaling regulates cell growth, differentiation, morphogenesis and apoptosis. TGF-β activated kinase 1 (TAK1) and Nemo-like kinase (NLK) function in Xenopus, Drosophila and C.elegans developments. Here we report that serine phosphorylation of STAT3 induced by TAK1-NLK cascade is essential for TGF-β-mediated mesoderm induction in Xenopus embryo. Depletion of TAK1, NLK or STAT3 blocks TGF-β-mediated mesoderm induction. Co-expression of NLK and STAT3 induces mesoderm by a mechanism that requires serine phosphorylation of STAT3. Activin activates NLK, which in turn directly phosphorylates STAT3. Moreover, depletion of either TAK1 or NLK inhibits endogenous serine phosphorylation of STAT3. These results provide the first evidence that TAK1-NLK-STAT3 cascade participates in TGF-β-mediated mesoderm induction.
    MAFbx/Atrogin-1 has been identified as a regulator for skeletal muscle atrophy, and encodes an F-box-type E3 ubiquitin ligase. However, little is known about how MAFbx/Atrogin-1 regulates cellular signaling. Here we identify and genetically characterize MFB-1, a MAFbx/Atrogin-1 homologue from Caenorhabditis elegans. The mfb-1 deletion mutant significantly enhanced the dauer constitutive (Daf-c) phenotype caused by mutations in the DAF-7/TrGF-β-like signaling pathway, but not the DAF-2/insulin receptor-like signaling pathway. Conversely, the Daf-c phenotypes of DAF-7 pathway mutants were partially suppressed by mfb-1 cDNA transgenes. Thus, MFB-1 acts genetically downstream in the DAF-7 pathway. A mfb-1 :: GFP fusion was found to be expressed in the nervous system, hypodermis and intestine, and overlapped expression of many DAF-7 pathway genes. We propose that MFB-1 is a novel F-box protein that negatively regulates dauer formation in concert with the DAF-7 signaling pathway in C.elegans.

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  • 負の増殖シグナルの異常と細胞増殖制御の破綻

    Grant number：12215154  2000 - 2004

    日本学術振興会  科学研究費助成事業  特定領域研究

    澁谷 浩司, 漆山 誠一, 白壁 恭子, 加藤 順也, 松尾 律子

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    Grant amount：\115400000 （ Direct Cost: \115400000 ）

    本研究ではがん発生過程に関わるTGF-βおよびWntシグナル分子の制御機能を解明するため、TGF-βおよびWntシグナルに関与する分子に相互作用する分子を単離し、研究を進めた。MAFbx/Atrogin1は筋萎縮に関与するユビキチンE3リガーゼである。我々はMAFbx/Atrogin1とTGF-βシグナルの関係を明らかにするため、その線虫相同遺伝子MFB-1を用いて遺伝学的機能解析を行った。MFB-1の生体内における機能を解析するため線虫mfb-1変異株を分離した。この変異体は単独では顕著な異常を示さなかったが、DAF-7経路においてシグナルを制御する遺伝子の変異体と二重変異にした際に、それらの変異体が単独で示す恒常的dauer形成(Daf-c)を顕著に増強させる表現型を示した。これに対して、dauer形成を制御するもう一つの経路として知られるDAF-2/インシュリン受容体様シグナル伝達経路におけるDAF-2変異体との二重変異では、そのDaf-c表現型に変化は見られなかった。逆にDAF-7経路のDaf-c変異体内でmfb-1遺伝子を過剰発現させた場合には、表現型を部分的に抑制できることも確認できた。また、DAF-7経路の変異体との二重変異で見られたDaf-cの増強は二重変異株へのmfb-1 cDNAの導入により、完全にレスキューされた。さらに、MFB-1におけるF-boxドメインを欠失させたmfb-1 cDNAについてレスキュー能を調べたところ、このcDNAはDAF-7経路の変異体との二重変異で見られるDaf-cの増強をレスキューできなかった。これはMFB-1のF-boxドメインが、機能上必須であることを示唆している。F-boxドメインはF-boxタンパク質がSCF複合体を形成する上で重要な領域と考えられており、MFB-1もユビキチンリガーゼとして機能していると考えられる。これらの結果からMFB-1は、遺伝学的にDAF-7経路のシグナルを正に制御し、線虫のdauer形成を抑制していることが明らかとなった。

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  • Regulation of TGF-b and Wnt signal interaction

    Grant number：12480218  2000 - 2001

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    SHIBUUYA Hiroshi

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    Grant amount：\14600000 （ Direct Cost: \14600000 ）

    The TGF-b superfamily has diverse biological activities and is involved in the early devel opment of animals. We previously identified a novel family member, BMP receptor associated molecule (BRAM), which binds to the intracellular domain of BMP type IA receptor and is involved in the BMP signaling pathway.
    To identify novel molecules involved in TGF-b signaling pathways, we performed yeast two-hybrid screening using BRAM as bait. From a Xenopus cDNA library, we cloned a cDNA encoding 693 amino acids and containing an oxysterol binding protein (OSBP) motif, which we designated BRAM interacting protein (BIP). We then isolated a BIP homologue from the C. elegans that encodes 733 amino acids and also contains the OSBP-like motif. Immunoprecipitation and Western blotting studies revealed that C. elegans BIP could interact with the C. elegans BRAM homologues, BRA-1 and BRA-2. C. elegans BIP was expressed in pharyngeal muscle, hypodermis and several neuronal cells, an expression pattern overlaps with those of BRA-1 and BRA-2. Finally, we found that inhibition of BIP expression in C. elegans by double stranded RNA interference produces a Sma phenotype.
    BIP was isolated using the yeast two-hybrid systems. BIP may function in TGF-b pathway and regulate body length in C. elegans.

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  • TGF-βスーパーファミリー受容体を介するシグナル伝達機構の解析

    Grant number：11139269  1999

    日本学術振興会  科学研究費助成事業  特定領域研究(A)

    澁谷 浩司

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    Grant amount：\2700000 （ Direct Cost: \2700000 ）

    TGF-βファミリーは、細胞膜上のセリン/スレオニンキナーゼ型受容体に結合した後、Smad経路によって核へシグナルが伝達される。リガンドが受容体に結合するとシグナル特異的Smadは受容体によりリン酸化を受け、Smad4と結合し核移行する。シグナル特異的SmadのC末端には受容体によってリン酸されるSSXSモチーフが存在する。
    本研究ではBMPシグナル伝達因子Smad8の選択的スプライシング産物Smad8BのBMPシグナル伝達系における役割を検討し、以下のことを明らかにした。
    1)Smad8Bは、Smad8のC末端の47アミノ酸が異なる4アミノ酸に置換したタンパク質として、選択的スプライシングにより発現されていると予想された。Smad8とSmad8Bは様々な組織で発現しているが、その発現量の比は組織によって異なっていることが明らかになった。
    2)Smad8BはSmad8とSmad4に特異的に結合し、また、BMPシグナルの存在に関わらず細胞質に局在することが明らかになった。
    3)Smad8Bは、BMPシグナルによるSmad8の活性化と標的遺伝子の発現誘導を特異的に抑制することが示された。
    以上の結果からSmad8Bは細胞質でSmad8やSmad4と複合体を形成し、Smad8の機能を特異的に抑制することによりBMP標的細胞のシグナル応答性を調節していることが示唆された。
    このようにSmadはリン酸化による修飾だけでなく、スプライシングによる発現制御や分解を受けることによっても、シグナルの応答性の調節に関与していることが示唆される。今後、このような制御機構を考慮しながら、Smadの生理的な役割を検討していくことが重要と考えられる。

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  • TGF-βシグナルに関与する転写因子の機能解析

    Grant number：11154229  1999

    日本学術振興会  科学研究費助成事業  特定領域研究(A)

    澁谷 浩司

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    Grant amount：\2100000 （ Direct Cost: \2100000 ）

    TGF-βファミリーとWntファミリーは共に生物の初期発生における形態形成や器官形成に関与していることが知られている。TGF-βシグナル因子であるSmadは受容体によりリン酸化され核へ移行、転写因子と複合体を形成し、標的遺伝子の転写を活性化する。一方、Wntシグナルが活性化されるとβ-cateninが細胞質内に蓄積し核へ移行、転写因子Lef1/TCFと複合体を形成し、標的遺伝子の転写を活性化する。
    XtwnはWntシグナルによって発現誘導されることが知られている。Xtwnプロモーターの欠失変異体を用いた解析からXtwnのプロモーター活性にはLEF1/TCF結合配列を含む領域以外に、さらに5'上流側領域の関与が明らかになった。また、Xtwnのプロモーター活性は不活性型Smad4を発現させることにより顕著に阻害された。XtwnプロモーターへのSmadの結合を検討した結果、SmadがLEF1/TCF結合配列の5'上流側に結合することが明らかになった。次に培養細胞系を用いて相互作用を検討したところ、Wntシグナル依存的な内在性のSmad4とβ-cateninの複合体形成が確認された。また、Wntシグナルでβーcateninが核移行した細胞でのみSmad4の核移行が観察された。したがって、Smad4はWntシグナルによって核移行し、LEF1/TCFやβ-cateninと複合体を形成することにより標的遺伝子の転写を協調的に活性化していることが示された。
    TGF-βシグナルの中心的な伝達因子として位置づけられていたSmad4がWntシグナル伝達系においても重要な役割を担っていることが示された。Smad4はXtwn遺伝子で限らず、多くのWntシグナル標的遺伝子に対しても関与していると考えられ、今後検討していく必要がある。

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  • TGF-βシグナルに関与する転写因子の機能解析

    Grant number：10173230  1998

    日本学術振興会  科学研究費助成事業  特定領域研究(A)

    澁谷 浩司

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    Grant amount：\2500000 （ Direct Cost: \2500000 ）

    BMPは骨、軟骨形成、発生、分化の形態形成において重要な役割を果している。マウス骨芽細胞株MC3T3-E1細胞より、BMP処理特異的に発現誘導される遺伝子としてDlx5を単離した。Dlx5は成熟マウスにおいてBMPの発現の高い脳と骨格組織に特異的な発現がみられた。またマウス胎児をin vitroでBMP処理し、Dlx5の発現を調べたところ、鰓弓に限局した顕著な発現誘導が観察された。BMPによるDlx5の発現誘導は組織レベルやin vivoの骨形成過程においても示された。CHXを用いた実験から、その発現誘導には新たなタンパク合成を必要としないBMP初期応答遺伝子であることもわかった。またDlx5を構成的に大量発現するMC3T3-E1骨芽細胞株を樹立したところ、骨形成に必須と考えられているCbfa-1の新たな発現誘導することなく高レベルのアルカリホスファターゼ活性に加え、コラーゲンやオステオカルシンといった細胞外マトリックス蛋白の生成量の顕著な増加がみられ、骨芽細胞分化が亢進していることがわかった。このことはBMPが少なくともDlx5発現誘導を介して骨芽細胞分化を誘導する可能性を示した。さらにはXenopus初期胚を用い、Dlx5を大量発現することによりBMPと同様な腹側中胚葉の誘導を引き起こせることも明らかとした。
    一方、TAK1とSmadのシグナル伝達経路上でのクロストークがATF2を介していることを見いだした。すなわち、TAK1はp38を介してATF2をリン酸化し、活性化する。またSmad3およびSmad4はATF2と複合体を形成し、PAI-1の様な標的遺伝子を活性化するのである。この事実はこれまでTAK1の作用とSmadの作用がある程度同様である(PAI-1の転写活性化等)ことが転写因子レベルでのクロストークであることを示している。

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  • Characterization of new genes for BMP signaling pathway.

    Grant number：09680714  1997 - 1998

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    SHIBUYA Hiroshi

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    Grant amount：\3700000 （ Direct Cost: \3700000 ）

    TAK1, a member of the MAP kinase kinase kinase family, and its activator, TAB1, participate in the bone morphogenetic protein (BMP) signaling pathway involved in mesoderm induction and patterning in early Xenopus embryos.However, the events leading from receptor activation to TAK1 activation remain to be identified.A yeast interaction screen was used to search for proteins that function in the pathway linking the receptors and TAB1-TAK1.The human X-chromosome-linked inhibitor of apoptosis protein (XIAP) was isolated as a TAB1-binding protein.XIAP associated not only with TAB1 but also with the BMP receptors in mammalian cells. Injection of XIAP mRNA into dorsal blastomeres enhanced the ventralization of Xenopus embryos in a TAB1-TAK1-dependent manner.Furthermore, a truncated form of XIAP lacking the TAB1-binding domain partially blocked the expression of ventral mesodermal marker genes induced by a constitutively-active BMP type I receptor.Taken together, we identified that XIAP participates in the BMP signaling pathway as a positive regulator linking the BMP receptors and TAB1-TAK1.
    Recently, we isolated a murine homeobox-containing gene, distal-less 5 (mDlx5), as a BMP-inducible gene in osteoblastic MC3T3-E1 cells.Stable transfectants of MC3T3-E1 that overexpress mDlx5 mRNA showed increase in various osteogenic markers ; a 4-fold increase in alkaline phosphatase activity, a 6-fold increase in osteocalcin production and appearance in mineralization of extracellular matrix.Furthermore, mDlx5 was induced orthotopically in mouse embryos treated with BMP-4 and in fractured bone of adult mice. Consistent with these observations, we also found that injection of mDlx5 mRNA in dorsal blastomeres enhanced the ventralization of Xenopus embryos.Our results indicated that mDlx5 is a target gene of the BMP signaling pathway and acts as an important regulator of both osteogenesis and dorso-ventral patterning of embryonic axis.

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  • TGF-βスーパーファミリー受容体を介するシグナル伝達機構の解析

    Grant number：09254201  1997

    日本学術振興会  科学研究費助成事業  重点領域研究

    澁谷 浩司

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    Grant amount：\2500000 （ Direct Cost: \2500000 ）

    BMP受容体会合分子BRAM2を培養細胞系に導入し、BMPやTGF-β受容体との会合特異性を検討したところ、BMPR-IA特異的に会合する分子であると考えられた。BRAM2はTAK1活性化因子TAB1とも結合しうることも明らかとなり、その結合領域はやはりBRAM2のC末側約100アミノ酸の領域であった。これらのことから、BRAM2はBMP受容体とTAK1を介したシグナル伝達系とを結ぶアンカー的役割を果たしているBMPシグナル分子であると考えられた。BMP受容体会合分子BRAM2がTAB1とも会合し、アンカー的な役割を果たしていることが予想されたが、その機能的な役割は明らかとなっていない。今後は果たしてBRAM2がシグナルをポジティブにもしくはネガティブに伝えているのかを検討していく必要がある。
    Differential display法を用いることにより、BMP刺激により誘導される遺伝子を探索し、マウスDlx-5を得た。マウスDlx-5mRNAは骨組織特異的に発現されており、他の組織では脳でわずかに見られるだけであった。またBMP刺激により速やかに発現誘導され、その転写誘導には新たなタンパク合成を必要としないことも明らかとなった。さらに骨折モデルマウスを用い、骨折部位の組織における骨再生過程でDlx-5が発現誘導されていることも明らかとした。Dlx-5発現細胞を骨芽細胞株MC3T3-E1で樹立した。得られた発現細胞のうちDlx-5高発現細胞株はBMP刺激することなく、骨分化マーカーの発現を誘導し、明らかな骨分化誘導が確認された。またこのとき骨分化に必要な転写因子であるCbfa-1の発現誘導は起こっていないことからDlx-5が骨分化誘導に必須な役割を果たしている新たな転写因子であることを明らかとした。BMPシグナルに呼応する標的遺伝子をDifferential display法を用いることにより、単離、同定し、Dlx-5が骨分化誘導能を有することを示した。このDlx-5がBMPの初期応答遺伝子であると考えられることから、シグナル分子TAK1やSmadの下流遺伝子である可能性も考えられ、この点を明らかにすることは興味あるところである。

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  • MOLECULAR MECHANISM FOR NEURAL FROMATION BY BMP

    Grant number：08458236  1996 - 1997

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    UENO Naoto, NAKAMURA Makoto, SHIBUYA Hiroshi

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    Grant amount：\7300000 （ Direct Cost: \7300000 ）

    Presumptive ectoderm gives rise to epidermal or naural tissues and the fate determination is made during gastrulation. Since after the experiments by Spemann and Mangold in 1920's showing that dorsal lip of amphibian can induce secondary body axis with neural tissues including brain and eyes when implanted in ventral side of host embryo, neural tissues are believed to be formed upon the induction triggered by factors emanated from the dorsal lip region of the embryo. However, recent studies on the function of polupeptide growth factors revealed that not epiudemal but neural formation is the ground state. Namely, ectodem is fated to become neural tissue is formed unless it is induced to become epidemis by BMP.Furthemore, it has recently been shown that neural induction takes place because BMP activity is inhibited by its binding proteins such as noggin and chordin.
    In this study, we have shown that follistatin which was originally known as an activin-binding protein, is able to bind BMP Thus follistatin inhibits epidermal inducging activity of BMP thereby induces neural fate. We further confirmed that tyhe interaction between follistatin and BMP and found that the dissociation of the complex is very fast, which makes detection of the interaction between follistatin and BMP and found that the dissociation of the complex is very fast, which makes detection of the interaction by conventional biochemical way difficult. The signal of BMP is mediated through cell surface ser/thr kinase recepotrs and intracellular mediators. To clarify the intyracellular signaling mechanism of BMP,we have screened for signaling moleculeS and target gene of BMP.We first identified a novel MAPKKK TAK1 as a mediater of BMP signal in Xenopus.Because overexpression of a dominant negative (kinase negatuive) TAK1 induced neural fate, TAK1 was suggested to be a mediatoR of BMP signal. We identified a homebox gene msx-1 as an immediate early gene responding to BMP-2 and BMP-4. We further confirmed that msx-1 overexpression leads to the phenotype reminicent to gain-of function of BMP.Our study has clarified a part of BMP signaling in the pathway of neural inhibition.

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  • TAK1はXenopus初期発生の背腹軸に関与する

    Grant number：7700000358  1995 - 1998

    科学技術振興機構  戦略的な研究開発の推進/戦略的創造研究推進事業/さきがけ

    澁谷 浩司

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    TGF-βの情報伝達を担うキナ-ゼであるTAK1は初期発生に重要な役割を担って いると考えられることから、ショウジョウバエやアフリカツメガエルをモデル動物として、このTAK1を介した情報伝達系の形態形成における役割を明らかにしていきます。

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  • Identification of transducer molecules for BMP signaling

    Grant number：07680733  1995 - 1996

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    SHIBUYA Hiroshi

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    Grant amount：\2100000 （ Direct Cost: \2100000 ）

    1. Identification of signal transducers binding to the cytoplasmic region of BMP type I receptor (BMPR-I). To clarify BMP receptor mediated signaling, the cytoplasmic interactors cDNAs of BMPR-I,which includes serine-threonine kinase, were isolated from human placenta cDNA library with the ose of a yeast two-hydrid system. The isolated 4 clones were termed to BRAM1-4 (BMP receptor associated molecule 1-4). We confirmed that BRAM2 interacted to catalytic domain of BMPR-I in yeast and mammalian cells. Moreover, BRAM2 also interacted to TGF-beta type I receptor.
    2. Identification of BMP-inducing molecules cDNA.To identify target genes for BMP signaling, we performed Differential display method using the mRNA prepared from MC3T3-E1 cells with or without BMP-stimulation, and Dlx-5 gene, which contains a homeotic box, were isolated. We confirmed that Dlx-5 gene was expressed by BMP-stimulation. The stable cell line which overexpressed Dlx-5, seems to lead the bone differentiation.

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  • The establishment of screening system to identify compoundsthat target BMP receptor-associated molecules

    Grant number：07557373  1995 - 1996

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (A)

    UENO Naoto, KATSUMATA Takashi, SHIBUYA Hiroshi

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    Grant amount：\1800000 （ Direct Cost: \1800000 ）

    In order to develop efficienct drugs that mimic the endogenous pathway of cytokines, precise molecular mechanism of signal transduction has to be clarified. Based on the mechanism, screening for compunds that modify the signaling pathway and thus act as agonist or antagonist can be achieved. TGF-beta activating kinase 1 (TAK1) and its activator, TAK1 binding protein 1 (TAB1) are implicated in TGF-beta and bone morphogenetic protein (BMP) signaling. However, the precise molecular mechanism by which ligand-ligated type I receptors induce TAB1 to activate TAK1 remains to be identified. To clarify BMP receptor mediated signaling, cytoplasmic interactors of BMP type Ia receptor (BMPRIa) were isolated with the use of a yeast two-hybrid system. One of the interactors isolated bound both TAB1 and BMPRIa in vivo. Sequence analysis revealed that this clone encoded a previously identified a denovirus E1A-associated protein, BS69. Although it contained E1A binding domain of BS69, NH2-terminal 12 amino acids of this clone were different from corresponding region of BS69. Therefore, we designated this molecule as BMP receptor associated molecule2 (BRAM2) and used in further experiments. The BRAM2 bound BMPRIa and TGF-beta type I receptor (TbetaRI) and augmented TAB1 binding to BMPRIa and TbetaRI in vivo. Furthermore, TAK1 and TAB1 mediated activation of plasminogen activator inhibitor-1 (PAI-1) gene promoter was strength ened by the expression of BRAM2. These results suggest that BRAM2 regulates the activity of TAB1 and is involved in TGF-beta and BMP signaling. Based on this knowledge, compunds that stimulate binding of BRAM2 to BMPR and may serve as agonists can now be screeened.

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