Researcher Database

Masamichi Imajo
Creative Research Institution Institute for Chemical Reaction Design and Discovery
Specially Appointed Associate Professor

Researcher Profile and Settings

Affiliation

  • Creative Research Institution Institute for Chemical Reaction Design and Discovery

Job Title

  • Specially Appointed Associate Professor

Degree

  • PhD(Kyoto University)

J-Global ID

Research Activities

Published Papers

  • Yu Muta, Michiyuki Matsuda, Masamichi Imajo, corresponding author
    Cancers 11 (4) 513  2019/04 [Refereed][Not invited]
  • Yu Muta, Michiyuki Matsuda, Masamichi Imajo, corresponding author
    Molecular & Cellular Oncology Informa {UK} Limited 5 (5) e1506684  2018/09 [Refereed][Not invited]
  • Transcriptional factor pancreatic duodenal homeobox-1 (Pdx1) is involved in age-related GIP hypersecretion in mice
    Eri Ikeguchi, Norio Harada, Yoshinori Kanemaru, Akiko Sankoda, Shunsuke Yamane, Kanako Iwasaki, Masamichi Imajo, Yuki Murata, Kazuyo Suzuki, Erina Joo, Nobuya Inagaki
    American Journal of Physiology Gastrointestinal and Liver Physiology 315 (2) G272 - G282 2018/08 [Refereed][Not invited]
  • Composite regulation of ERK activity dynamics underlying tumour-specific traits in the intestine
    Yu Muta, Yoshihisa Fujita, Kenta Sumiyama, Atsuro Sakurai, Makoto M. Taketo, Tsutomu Chiba, Hiroshi Seno, Kazuhiro Aoki, Michiyuki Matsuda, Masamichi Imajo, corresponding author
    Nature Communications 9 (1) 2174 - 2174 2018/06 [Refereed][Not invited]
  • Yumi Konagaya, Kenta Terai, Yusuke Hirao, Kanako Takakura, Masamichi Imajo, Yuji Kamioka, Norio Sasaoka, Akira Kakizuka, Kenta Sumiyama, Tomoichiro Asano, Michiyuki Matsuda
    CELL REPORTS 21 (9) 2628 - 2638 2211-1247 2017/11 [Refereed][Not invited]
     
    AMP-activated protein kinase (AMPK), a master regulator of cellular metabolism, is a potential target for type 2 diabetes. Although extensive in vitro studies have revealed the complex regulation of AMPK, much remains unknown about the regulation in vivo. We therefore developed transgenic mice expressing a highly sensitive fluorescence resonance energy transfer (FRET)-based biosensor for AMPK, called AMPKAR-EV. AMPKAR-EV allowed us to readily examine the role of LKB1, a canonical stimulator of AMPK, in drug-induced activation and inactivation of AMPK in vitro. In transgenic mice expressing AMPKAR-EV, the AMP analog AICAR activated AMPK in muscle. In contrast, the antidiabetic drug metformin activated AMPK in liver, highlighting the organ-specific action of AMPK stimulators. Moreover, we found that AMPK was activated primarily in fast-twitch muscle fibers after tetanic contraction and exercise. These observations suggest that the AMPKAR-EV mouse will pave a way to understanding the heterogeneous responses of AMPK among cell types in vivo.
  • Antagonistic Interactions between Extracellular Signal-Regulated Kinase Mitogen-Activated Protein Kinase and Retinoic Acid Receptor Signaling in Colorectal Cancer Cells
    Masamichi Imajo, Kunio Kondoh, Takuya Yamamoto, Kei Nakayama, May Nakajima-Koyama, Eisuke Nishida, corresponding author
    Molecular and Cellular Biology 37 (15) e00012-17  2017/07 [Refereed][Not invited]
  • T. Hiratsuka, T. Sano, H. Kato, N. Komatsu, M. Imajo, Y. Kamioka, K. Sumiyama, F. Banno, T. Miyata, M. Matsuda
    JOURNAL OF THROMBOSIS AND HAEMOSTASIS 15 (7) 1487 - 1499 1538-7933 2017/07 [Refereed][Not invited]
     
    Background: The dynamic features of thrombus formation have been visualized by conventional video widefield microscopy or confocal microscopy in live mice. However, owing to technical limitations, the precise spatiotemporal regulation of intracellular signaling molecule activities, which have been extensively studied in vitro, remains elusive in vivo. Objectives: To visualize, by the use of two-photon excitation microscopy of transgenic mice expressing Forster resonance energy transfer (FRET) biosensors for extracellular signal-regulated kinase (ERK) and protein kinase A (PKA), ERK and PKA activities during thrombus formation in laser-injured subcutaneous arterioles. Results: When a core of densely packed platelets had developed, ERK activity was increased from the basal region close to the injured arterioles. PKA was activated at the downstream side of an unstable shell overlaying the core of platelets. Intravenous administration of a MEK inhibitor, PD0325901, suppressed platelet tethering and dislodged platelet aggregates, indicating that ERK activity is indispensable for both initiation and maintenance of the thrombus. A cAMP analog, dbcAMP, inhibited platelet tethering but failed to dislodge the preformed platelet aggregates, suggesting that PKA can antagonize thrombus formation only in the early phase. Conclusion: In vivo imaging of transgenic mice expressing FRET biosensors will open a new opportunity to visualize the spatiotemporal changes in signaling molecule activities not only during thrombus formation but also in other hematologic disorders.
  • Cell competition with normal epithelial cells promotes apical extrusion of transformed cells through metabolic changes
    Shunsuke Kon, Kojiro Ishibashi, Hiroto Katoh, Sho Kitamoto, Mihoko Kajita, Susumu Ishikawa, Hajime Yamauchi, Yuta Yako, Tomoko Kamasaki, Tomohiro Matsumoto, Hirotaka Watanabe, Riku Egami, Ayana Sasaki, Atsuko Nishikawa, Ikumi Kameda, Takeshi Maruyama, Yoshiteru Sasaki, Ryosuke Enoki, Sato Honma, Hiromi Imamura, Masanobu Oshima, Tomoyoshi Soga, Jun-ichi Miyazaki, Toshiro Sato, Michael Duchen, Takanobu Shirai, Shinya Tanaka, Rika Narumi, Tomoko Morita, Jin-Min Nam, Yasuhito Onodera, Shingo Yoshioka, Junichi Kikuta, Masaru Ishii, Masamichi Imajo, Eisuke Nishida, Yoichiro Fujioka, Yusuke Ohba, Yasuyuki Fujita
    Nature Cell Biology 19 530 - 541 2017/05 [Refereed][Not invited]
  • Yoshihisa Okuchi, Masamichi Imajo, Rei Mizuno, Yuji Kamioka, Hiroyuki Miyoshi, Makoto Mark Taketo, Satoshi Nagayama, Yoshiharu Sakai, Michiyuki Matsuda
    PLOS ONE 11 (9) 1932-6203 2016/09 [Refereed][Not invited]
     
    Aging-associated alterations of cellular functions have been implicated in various disorders including cancers. Due to difficulties in identifying aging cells in living tissues, most studies have focused on aging-associated changes in whole tissues or certain cell pools. Thus, it remains unclear what kinds of alterations accumulate in each cell during aging. While analyzing several mouse lines expressing fluorescent proteins (FPs), we found that expression of FPs is gradually silenced in the intestinal epithelium during aging in units of single crypt composed of clonal stem cell progeny. The cells with low FP expression retained the wildtype Apc allele and the tissues composed of them did not exhibit any histological abnormality. Notably, the silencing of FPs was also observed in intestinal adenomas and the surrounding normal mucosae of Apc-mutant mice, and mediated by DNA methylation of the upstream promoter. Our genome-wide analysis then showed that the silencing of FPs reflects specific gene expression alterations during aging, and that these alterations occur in not only mouse adenomas but also human sporadic and hereditary (familial adenomatous polyposis) adenomas. Importantly, pharmacological inhibition of DNA methylation, which suppresses adenoma development in Apc-mutant mice, reverted the aging-associated silencing of FPs and gene expression alterations. These results identify aging-associated gene expression signatures that are heterogeneously induced by DNA methylation and precede intestinal tumorigenesis triggered by Apc inactivation, and suggest that pharmacological inhibition of the signature genes could be a novel strategy for the prevention and treatment of intestinal tumors.
  • Paloma Ordonez-Moran, Caroline Dafflon, Masamichi Imajo, Eisuke Nishida, Joerg Huelsken
    CANCER CELL 28 (6) 815 - 829 1535-6108 2015/12 [Refereed][Not invited]
     
    Hierarchical organization of tissues relies on stem cells, which either self-renew or produce committed progenitors predestined for lineage differentiation. Here we identify HOXA5 as an important repressor of intestinal stem cell fate in vivo and identify a reciprocal feedback between HOXA5 and Wnt signaling. HOXA5 is suppressed by the Wnt pathway to maintain stemness and becomes active only outside the intestinal crypt where it inhibits Wnt signaling to enforce differentiation. In colon cancer, HOXA5 is downregulated, and its re-expression induces loss of the cancer stem cell phenotype, preventing tumor progression and metastasis. Tumor regression by HOXA5 induction can be triggered by retinoids, which represent tangible means to treat colon cancer by eliminating cancer stem cells.
  • Masamichi Imajo, Miki Ebisuya, Eisuke Nishida
    NATURE CELL BIOLOGY 17 (1) 7 - + 1465-7392 2015/01 [Refereed][Not invited]
     
    The rapidly self-renewing intestinal epithelium represents an exquisite model for stem cell biology. So far, genetic studies in mice have uncovered crucial roles for several signalling pathways in the tissue. Here we show, by using intestine-specific gene transfer (iGT), that Hippo signalling effectors, YAP and TAZ, promote both the proliferation of intestinal stem/progenitor cells and their differentiation into goblet cells. These functions of YAP/TAZ are regulated by the upstream Hippo pathway kinases MST1/2 and LATS1/2. Moreover, we identify TEADs and Klf4 as partner transcription factors of YAP/TAZ in the proliferation and differentiation processes, respectively. These results indicate that Hippo signalling plays a dual role in renewal of the intestinal epithelium through the regulation of two different processes, stem/progenitor cell proliferation and differentiation into goblet cells, using two different types of transcription factor. Moreover, iGT should provide a robust platform to elucidate molecular mechanisms of intestinal epithelium self-renewal.
  • HVJ-E-mediated gene transfer into the intestinal epithelium
    M. Imajo, M. Ebisuya, E. Nishida
    Protocol Exchange doi: 10.1038/protex.2014.049 2014/12 [Not refereed][Not invited]
  • Rei Mizuno, Yuji Kamioka, Kenji Kabashima, Masamichi Imajo, Kenta Sumiyama, Eiji Nakasho, Takeshi Ito, Yoko Hamazaki, Yoshihisa Okuchi, Yoshiharu Sakai, Etsuko Kiyokawa, Michiyuki Matsuda
    JOURNAL OF EXPERIMENTAL MEDICINE 211 (6) 1123 - 1136 0022-1007 2014/06 [Refereed][Not invited]
     
    Many chemical mediators regulate neutrophil recruitment to inflammatory sites. Although the actions of each chemical mediator have been demonstrated with neutrophils in vitro, how such chemical mediators act cooperatively or counteractively in vivo remains largely unknown. Here, by in vivo two-photon excitation microscopy with transgenic mice expressing biosensors based on Frster resonance energy transfer, we time-lapse-imaged the activities of extracellular signal-regulated kinase (ERK) and protein kinase A (PKA) in neutrophils in inflamed intestinal tissue. ERK activity in neutrophils rapidly increased during spreading on the endothelial cells and showed positive correlation with the migration velocity on endothelial cells or in interstitial tissue. Meanwhile, in the neutrophils migrating in the interstitial tissue, high PKA activity correlated negatively with migration velocity. In contradiction to previous in vitro studies that showed ERK activation by prostaglandin E-2 (PGE(2)) engagement with prostaglandin receptor EP4, intravenous administration of EP4 agonist activated PKA, inhibited ERK, and suppressed migration of neutrophils. The opposite results were obtained using nonsteroidal antiinflammatory drugs (NSAIDs). Therefore, NSAID-induced enteritis may be caused at least partially by the inhibition of EP4 receptor signaling of neutrophils. Our results demonstrate that ERK positively regulates the neutrophil recruitment cascade by promoting adhesion and migration steps.
  • Masamichi Imajo, Koichi Miyatake, Akira Iimura, Atsumu Miyamoto, Eisuke Nishida
    EMBO JOURNAL 31 (5) 1109 - 1122 0261-4189 2012/03 [Refereed][Not invited]
     
    The Hippo signalling pathway has emerged as a key regulator of organ size, tissue homeostasis, and patterning. Recent studies have shown that two effectors in this pathway, YAP/TAZ, modulate Wnt/beta-catenin signalling through their interaction with beta-catenin or Dishevelled, depending on biological contexts. Here, we identify a novel mechanism through which Hippo signalling inhibits Wnt/beta-catenin signalling. We show that YAP and TAZ, the transcriptional co-activators in the Hippo pathway, suppress Wnt signalling without suppressing the stability of beta-catenin but through preventing its nuclear translocation. Our results show that YAP/TAZ binds to beta-catenin, thereby suppressing Wnt-target gene expression, and that the Hippo pathway-stimulated phosphorylation of YAP, which induces cytoplasmic translocation of YAP, is required for the YAP-mediated inhibition of Wnt/beta-catenin signalling. We also find that downregulation of Hippo signalling correlates with upregulation of beta-catenin signalling in colorectal cancers. Remarkably, our analysis demonstrates that phosphorylated YAP suppresses nuclear translocation of beta-catenin by directly binding to it in the cytoplasm. These results provide a novel mechanism, in which Hippo signalling antagonizes Wnt signalling by regulating nuclear translocation of b-catenin. The EMBO Journal ( 2012) 31, 1109-1122. doi: 10.1038/emboj.2011.487; Published online 10 January 2012
  • Masamichi Imajo, Eisuke Nishida
    GENES TO CELLS 15 (10) 1089 - 1097 1356-9597 2010/10 [Refereed][Not invited]
     
    Tribbles encode an evolutionarily conserved protein family that regulates cell proliferation, motility, metabolism and oncogenic transformation. Emerging evidence suggests that Tribbles function as adaptor or scaffold proteins to facilitate the degradation of their target proteins and to control the activation of various key signaling pathways. In this study, we uncover a novel function of human Tribbles homolog 1 (Trib1) as a regulator of retinoic acid receptor (RAR) signaling. We show that shRNA-mediated knockdown of Trib1 promotes transcriptional activity of RARs, leading to enhanced expression of endogenous RAR-target genes. Moreover, our results show that Trib1 directly interacts with RAR alpha and retinoid X receptor-alpha (RXR alpha) through its kinase-like domain. Consistently, Trib1 colocalizes with RAR alpha and RXR alpha in the nucleus. Biochemical analyses show that the ligand-binding domain (LBD) of RAR alpha mediates the interaction with Trib1. Ligand treatment, however, does not affect the binding of Trib1 to RAR alpha/RXR alpha. Furthermore, a putative LXXLL motif, which is a potential LBD-binding site and locates in the kinase-like domain of Trib1, is not required for the binding. These results suggest a unique feature of the binding. Taken together, these results suggest that Trib1 functions as a negative regulator of RARs and shed new light on the molecular mechanisms for nuclear receptor-mediated transcriptional repression.
  • M Imajo, Y Tsuchiya, E Nishida
    IUBMB LIFE 58 (5-6) 312 - 317 1521-6543 2006/05 [Refereed][Not invited]
     
    Mitogen-activated protein kinase (MAPK) pathways play central roles in controlling diverse cellular functions. They are finely regulated by several mechanisms, including scaffolding of their components, and phosphorylation/dephosphorylation and compartmentalization of MAPKs. A number of molecules have been identified as regulators involved in these mechanisms. They modulate the magnitude and the specificity of MAPK signaling, and thereby regulate the wide variety of signaling outputs. Recent studies have identified novel functions of the MAPK signaling pathways. It is becoming clear that strict regulation of the MAPK pathways underlies their manifold functions in numerous biological processes.

Books etc

  • Experimental Medicine Vol.33 No.18 (November) 2015
    Masamichi Imajo, Eisuke Nishida (ContributorRole of Hippo signaling in controlling intestinal homeostasis)
    Yodosha CO., LTD. 2015/11
  • 「生体の科学」66巻5号
    今城 正道 (Contributor26. Wntシグナル)
    公益財団法人金原一郎記念医学医療振興財団「生体の科学」編集室 2015

Conference Activities & Talks

  • Analysis of molecular mechanisms underlying development of hepatoblastoma by using a novel organoid culture system  [Not invited]
    Masamichi Imajo, Michiyuki Matsuda
    The 68th Annual Meeting of the Japan Society for Cell Biology  2016/06
  • Role of the Hippo pathsay in stem cell-driven renewal of the intestinal epithelium  [Invited]
    Masamichi Imajo, Eisuke Nishida
    Biochemistry and Molecular Biology (BMB) 2015  2015/12
  • 組織幹細胞の制御におけるHippo経路の新たな役割  [Invited]
    今城 正道
    第8回Symphony  2015/09
  • Novel regulatory mechanisms of intestinal stem cell function revealed by in vivo gene transfer  [Invited]
    Masamichi Imajo
    The 66th Annual Meeting of the Japanese Society for Cell Biology  2014/06  奈良県新公会堂  The Japanese Society for Cell Biology
  • Analysis on the signal transduction network controlling intestinal homeostasis  [Invited]
    Masamichi Imajo, Eisuke Nishida
    The 84th Annual Meeting of the Japanese Biochemical Society  2011/09  日本生化学会


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