TSUKASA OIKAWA
| Faculty of Medicine Physiological Science Biochemistry | Lecturer |
Last Updated :2025/06/07
■Researcher basic information
Researchmap personal page
Home Page URL
Researcher number
- 20457055
J-Global ID
Research Field
Educational Organization
- Bachelor's degree program, Departments of Medicine, School of Medicine
- Master's degree program, Graduate School of Medicine
- Doctoral (PhD) degree program, Graduate School of Medicine
■Career
Career
- Oct. 2014
Hokkaido University, Assistant Professor - Aug. 2013 - Sep. 2014
Hokkaido University Graduate School of Medicine, Department of Molecular Biology, 特任講師 - Jan. 2009 - Jul. 2013
Keio University School of Medicine, 特任講師 - Apr. 2007 - Dec. 2008
Kobe University Graduate School of Medicine, Lipid Biochemistry
Educational Background
■Research activity information
Papers
- Mechanical control of osteoclast fusion by membrane-cortex attachment and BAR proteins.
Yumeng Wan, Yuri L Nemoto, Tsukasa Oikawa, Kazunori Takano, Takahiro K Fujiwara, Kazuya Tsujita, Toshiki Itoh
The Journal of cell biology, 224, 7, 07 Jul. 2025, [Peer-reviewed], [International Magazine]
English, Scientific journal, Osteoclasts are multinucleated giant cells that are formed by the fusion of precursor cells. Cell-cell fusion is mediated by membrane protrusion driven by actin reorganization, but the role of membrane mechanics in this process is unknown. Utilizing live-cell imaging, optical tweezers, manipulation of membrane-to-cortex attachment (MCA), and genetic interference, we show that a decrease in plasma membrane (PM) tension is a mechanical prerequisite for osteoclast fusion. Upon RANKL-induced differentiation, ezrin expression in fusion progenitor cells is reduced, resulting in a decrease in MCA-dependent PM tension. A forced elevation of PM tension by reinforcing the MCA conversely suppresses cell-cell fusion. Mechanistically, reduced PM tension leads to membrane protrusive invadosome formation driven by membrane curvature-inducing/sensing BAR proteins, thereby promoting cell-cell fusion. These findings provide insights into the mechanism of cell-cell fusion under the control of membrane mechanics. - Development of a Myogenin minimal promoter-based system for visualizing the degree of myogenic differentiation
Yoshizuki Fumoto, Shingo Takada, Yasuhito Onodera, Shigetsugu Hatakeyama, Tsukasa Oikawa
Biochemical and Biophysical Research Communications, 741, 151091, 151091, Elsevier BV, Dec. 2024, [Peer-reviewed], [Last author, Corresponding author]
Scientific journal, 48075244 - Spatial confinement induces reciprocating migration of epidermal keratinocytes and forms triphasic epithelia
Takuma Nohara, Junichi Kumamoto, Yosuke Mai, Mayuna Shimano, Sora Kato, Hiroyuki Kitahata, Hideki Nakamura, Shota Takashima, Mika Watanabe, Masaharu Nagayama, Tsukasa Oikawa, Hideyuki Ujiie, Ken Natsuga
bioRxiv, Cold Spring Harbor Laboratory, 13 Nov. 2024
Epithelial cells undergo epithelial–mesenchymal transition (EMT) during migration and regain their epithelial phenotype in the post-migration phase (mesenchymal–epithelial transition; MET). We established an experimental system that reproduced three-dimensional triphasic epithelia, i.e., the original epithelium, its EMT, and MET. Keratinocytes (KCs), skin epithelial cells, placed on a microporous membrane migrated through 3.0-um or larger micropores. The 3.0-um-pored membrane induced an epithelial structure with three states: stratified KCs above the membrane, KCs showing EMT within the micropores, and a new stratified epithelium under the membrane. The membrane with larger micropores failed to maintain the triphasic epithelia. Live imaging revealed that KCs moved in a reciprocating manner, with actin-rich filopodia-like KC structures extending into and out of the 3.0-um micropores, while the cells migrated unidirectionally into larger micropores. Piezo1 and keratin 6 were identified as negative modulators of KC entry to and exit from the 3.0-um micropores. These results demonstrate that non-cancerous epithelial cells migrate through confined spaces in a reciprocating manner, which might help form triphasic epithelia, recapitulating wound healing processes. - p53 ensures the normal behavior and modification of G1/S-specific histone H3.1 in the nucleus
Tsukasa Oikawa, Junya Hasegawa, Haruka Handa, Naomi Ohnishi, Yasuhito Onodera, Ari Hashimoto, Junko Sasaki, Takehiko Sasaki, Koji Ueda, Hisataka Sabe
Life Science Alliance, 7, 9, e202402835, Sep. 2024, [Peer-reviewed], [Lead author, Corresponding author]
English, Scientific journal, 27679170 - MitoNEET reduces the mitochondrial oxidative phosphorylation during epithelial-mesenchymal transition
Haruka Handa, Yasuhito Onodera, Tsukasa Oikawa, Shingo Takada, Koji Ueda, Daiki Setoyama, Takashi Yokota, Miwako Yamasaki, Masahiko Watanabe, Yoshizuki Fumoto, Ari Hashimoto, Soichiro Hata, Masaaki Murakami, Hisataka Sabe
bioRxiv, Cold Spring Harbor Laboratory, 29 Jul. 2024
Mitochondrial functions range from catabolic to anabolic, which are tightly coordinated to meet cellular demands for proliferation and motility. MitoNEET is a mitochondrial outer membrane protein with a CDGSH domain and is involved in mitochondrial function. Epithelial-to-mesenchymal transition (EMT) is the process in which cells lose their epithelial characteristics and acquire mesenchymal traits, such as motility, which is a vital step for organism development and wound-healing. Cellular motility is associated with high ATP consumption owing to lamellipodia formation, which is supported by upregulated oxidative phosphorylation (OXPHOS) capacity. However, how mitoNEET is involved in the regulation of OXPHOS capacity and subsequent cellular motility remains unclear. Here we show that loss of mitoNEET regulation during EMT impairs both OXPHOS enhancement and cell motility in non-transformed NMuMG mouse mammary gland epithelial cells. We found that mitoNEET is downregulated during EMT, and that the aberrant expression of mitoNEET abolishes the upregulation of OXPHOS, leading to the inhibition of cell motility. Furthermore, we found that mitoNEET topology may be crucial for the regulation of the mitochondrial electron transfer chain, suggesting an additional regulatory pathway for OXPHOS capacity. Our results demonstrate that mitochondrial OXPHOS capacity during EMT is partly regulated by the dynamics of the outer membrane protein. We believe that our findings are the first step towards understanding the mechanisms by which mitochondrial outer membrane protein topology affects organelle functions - p53 secures the normal behavior of H3.1 histone in the nucleus by regulating nuclear phosphatidic acid and EZH2 during the G1/S phase
Tsukasa Oikawa, Junya Hasegawa, Haruka Handa, Naomi Ohnishi, Yasuhito Onodera, Ari Hashimoto, Junko Sasaki, Takehiko Sasaki, Koji Ueda, Hisataka Sabe
bioRxiv, Cold Spring Harbor Laboratory, 28 Jun. 2023, [Lead author, Corresponding author]
English, Scientific journal, Abstract
Histones are key molecules of epigenetic regulation and inheritance, and are thought to be chaperoned and transported into the nucleus appropriately prior to being integrated into nucleosomes. H3.1 histone is predominantly synthesized and enters the nucleus during the G1/S phase of the cell cycle, as a new component of duplicating nucleosomes. Here we found that p53 is necessary to secure the normal behavior and modification of H3.1 in the nucleus during the G1/S phase, in which p53 increases C-terminal domain nuclear envelope phosphatase 1 (CTDNEP1) levels and decreases enhancer of zeste homolog 2 (EZH2) levels in the H3.1 interactome. In the absence of p53, H3.1 molecules tended to be tethered at or near the nuclear envelope (NE), where they were predominantly trimethylated at lysine 27 (H3K27me3) by EZH2, without forming nucleosomes. This accumulation was likely caused by the high affinity of H3.1 towards phosphatidic acid (PA). p53 reduced nuclear PA levels by increasing levels of CTDNEP1, which activates lipin to convert PA into diacylglycerol. Induction of theTMEM255Agene by p53 linked p53 with CTDNEP1, in which TMEM255A stabilized CTDNEP1. We moreover found that the cytosolic H3 chaperone HSC70 attenuates the H3.1-PA interaction, and our molecular imaging analyses suggested that H3.1 molecules may be anchored around the NE after their nuclear entry. Our results expand our knowledge of p53 function in regulation of the nuclear behavior of H3.1 during the G1/S phase, in which p53 may primarily target nuclear PA and EZH2., 27679170 - Dupuytren's contracture-associated SNPs increase SFRP4 expression in nonimmune cells including fibroblasts to enhance inflammation development.
Hiroaki Kida, Jing-Jing Jiang, Yuichiro Matsui, Ikuko Takahashi, Rie Hasebe, Daisuke Kawamura, Takeshi Endo, Hiroki Shibayama, Makoto Kondoh, Yasuhiko Nishio, Kinya Nishida, Yoshihiro Matsuno, Tsukasa Oikawa, Shimpei Kubota, Shintaro Hojyo, Norimasa Iwasaki, Shigeru Hashimoto, Yuki Tanaka, Masaaki Murakami
International immunology, 31 Jan. 2023, [Peer-reviewed], [International Magazine]
English, Scientific journal, Dupuytren's contracture (DC) is an inflammatory fibrosis characterized by fibroproliferative disorders of the palmar aponeurosis, for which there is no effective treatment. Although several genome-wide association studies have identified risk alleles associated with DC, the functional linkage between these alleles and the pathogenesis remains elusive. We here focused on two SNPs associated with DC, rs16879765 and rs17171229, in secreted frizzled related protein 4 (SFRP4). We investigated the association of SRFP4 with the IL-6 amplifier, which amplifies the production of IL-6, growth factors, and chemokines in non-immune cells and aggravates inflammatory diseases via NF-κB enhancement. Knockdown of SFRP4 suppressed activation of the IL-6 amplifier in vitro and in vivo, whereas the overexpression of SFRP4 induced the activation of NF-κB-mediated transcription activity. Mechanistically, SFRP4 induced NF-κB activation by directly binding to molecules of the ubiquitination SFC complex, such as IkBα and βTrCP, followed by IkBα degradation. Furthermore, SFRP4 expression was significantly increased in fibroblasts derived from DC patients bearing the risk alleles. Consistently, fibroblasts with the risk alleles enhanced activation of the IL-6 amplifier. These findings indicate that the IL-6 amplifier is involved in the pathogenesis of DC, particularly in patients harboring the SFRP4 risk alleles. Therefore, SFRP4 is a potential therapeutic target for various inflammatory diseases and disorders, including DC. - Type XVII collagen interacts with the aPKC-PAR complex and maintains epidermal cell polarity.
Mika Watanabe, Hideyuki Kosumi, Shin-Ichi Osada, Shota Takashima, Yunan Wang, Wataru Nishie, Tsukasa Oikawa, Tomonori Hirose, Hiroshi Shimizu, Ken Natsuga
Experimental dermatology, 30, 1, 62, 67, Jan. 2021, [Peer-reviewed], [International Magazine]
English, Scientific journal, Type XVII collagen (COL17) is a transmembrane protein expressed in the basal epidermis. COL17 serves as a niche for epidermal stem cells, and although its reduction has been implicated in altering cell polarity and ageing of the epidermis, it is unknown how COL17 affects epidermal cell polarity. Here, we uncovered COL17 as a binding partner of the aPKC-PAR complex, which is a key regulating factor of cell polarity. Immunoprecipitation-immunoblot assay and protein-protein binding assay revealed that COL17 interacts with aPKC and PAR3. COL17 deficiency or epidermis-specific aPKCλ deletion destabilized PAR3 distribution in the epidermis, while aPKCζ knockout did not. Asymmetrical cell division was pronounced in COL17-null neonatal paw epidermis. These results show that COL17 is pivotal for maintaining epidermal cell polarity. Our study highlights the previously unrecognized role of COL17 in the basal keratinocytes. - ARF6 and AMAP1 are major targets of KRAS and TP53 mutations to promote invasion, PD-L1 dynamics, and immune evasion of pancreatic cancer
Shigeru Hashimoto, Shotaro Furukawa, Ari Hashimoto, Akio Tsutaho, Akira Fukao, Yurika Sakamura, Gyanu Parajuli, Yasuhito Onodera, Yutaro Otsuka, Haruka Handa, Tsukasa Oikawa, Soichiro Hata, Yoshihiro Nishikawa, Yusuke Mizukami, Yuzo Kodama, Masaaki Murakami, Toshinobu Fujiwara, Satoshi Hirano, Hisataka Sabe
Proceedings of the National Academy of Sciences of the United States of America, 116, 35, 17450, 17459, 27 Aug. 2019, [Peer-reviewed]
Scientific journal - Epithelial-specific histone modification of the miR-96/182 locus targeting AMAP1 mRNA predisposes p53 to suppress cell invasion in epithelial cells.
Handa H, Hashimoto A, Hashimoto S, Sugino H, Oikawa T, Sabe H
Cell communication and signaling : CCS, 16, 1, 94, 94, Dec. 2018, [Peer-reviewed], [International Magazine]
English, Scientific journal, BACKGROUND: TP53 mutations in cancer cells often evoke cell invasiveness, whereas fibroblasts show invasiveness in the presence of intact TP53. AMAP1 (also called DDEF1 or ASAP1) is a downstream effector of ARF6 and is essential for the ARF6-driven cell-invasive phenotype. We found that AMAP1 levels are under the control of p53 (TP53 gene product) in epithelial cells but not in fibroblasts, and here addressed that molecular basis of the epithelial-specific function of p53 in suppressing invasiveness via targeting AMAP1. METHODS: Using MDA-MB-231 cells expressing wild-type and p53 mutants, we identified miRNAs in which their expression is controlled by normal-p53. Among them, we identified miRNAs that target AMAP1 mRNA, and analyzed their expression levels and epigenetic statuses in epithelial cells and nonepithelial cells. RESULTS: We found that normal-p53 suppresses AMAP1 mRNA in cancer cells and normal epithelial cells, and that more than 30 miRNAs are induced by normal-p53. Among them, miR-96 and miR-182 were found to target the 3'-untranslated region of AMAP1 mRNA. Fibroblasts did not express these miRNAs at detectable levels. The ENCODE dataset demonstrated that the promoter region of the miR-183-96-182 cistron is enriched with H3K27 acetylation in epithelial cells, whereas this locus is enriched with H3K27 trimethylation in fibroblasts and other non-epithelial cells. miRNAs, such as miR-423, which are under the control of p53 but not associated with AMAP1 mRNA, demonstrated similar histone modifications at their gene loci in epithelial cells and fibroblasts, and were expressed in these cells. CONCLUSION: Histone modifications of certain miRNA loci, such as the miR-183-96-182 cistron, are different between epithelial cells and non-epithelial cells. Such epithelial-specific miRNA regulation appears to provide the molecular basis for the epithelial-specific function of p53 in suppressing ARF6-driven invasiveness. - P53-dependent and -independent epithelial integrity: Beyond miRNAs and metabolic fluctuations
Tsukasa Oikawa, Yutaro Otsuka, Hisataka Sabe
Cancers, 10, 6, E162, MDPI AG, 01 Jun. 2018, [Peer-reviewed], [Lead author]
English, Scientific journal, 27679173 - Frequent overexpression of AMAP1, an Arf6 effector in cell invasion, is characteristic of the MMTV-PyMT rather than the MMTV-Neu human breast cancer model
Yutaro Otsuka, Tsukasa Oikawa, Hinako Yoshino, Shigeru Hashimoto, Haruka Handa, Hiroki Yamamoto, Ari Hashimoto, Hisataka Sabe
Cell Communication and Signaling, 16, 1, 1, BioMed Central Ltd., 05 Jan. 2018, [Peer-reviewed], [Corresponding author]
English, Scientific journal - Necessity of p53-binding to the CDH1 locus for its expression defines two epithelial cell types differing in their integrity.
Oikawa T, Otsuka Y, Onodera Y, Horikawa M, Handa H, Hashimoto S, Suzuki Y, Sabe H
Scientific reports, 8, 1, 1595, 1595, Jan. 2018, [Peer-reviewed], [Lead author], [International Magazine]
English, Scientific journal, TP53 mutation (i.e., loss of normal-p53) may evoke epithelial-mesenchymal transition (EMT), which was previously attributed to loss of certain miRNAs. However, not all epithelial cells undergo EMT upon TP53 mutation, and the p53-miRNA axis may not fully explain p53 function in epithelial integrity. We here show two modes of epithelial integrity: one involves p53-binding to a nucleotide region and the other does not. In the former, p53 binds to the CDH1 (encoding E-cadherin) locus to antagonize EZH2-mediated H3K27 trimethylation (H3K27me3) to maintain high levels of acetylation of H3K27 (H3K27ac). In the latter, the same locus is not highly acetylated at H3K27, and does not allow p53-binding, nor needs to antagonize EZH2. We moreover demonstrated that although the CDH1 locus in the p53-independent cells, but not in fibroblasts, becomes high-H3K27ac by butyrate and allows p53-biniding, their CDH1 expression does not become dependent on p53. Our results identified novel modes of the epithelial integrity, in which the same epithelial-specific gene locus exhibits different requirement for p53 with different histone modifications among different epithelial cells to warrant its expression., 27679173 - ARF1 recruits RAC1 to leading edge in neutrophil chemotaxis
Yuichi Mazaki, Yasuhito Onodera, Tsunehito Higashi, Takahiro Horinouchi, Tsukasa Oikawa, Hisataka Sabe
CELL COMMUNICATION AND SIGNALING, 15, 1, 36, Oct. 2017, [Peer-reviewed]
English, Scientific journal - High expression of EPB41L5, an integral component of the Arf6-driven mesenchymal program, correlates with poor prognosis of squamous cell carcinoma of the tongue
Yutaro Otsuka, Hiroki Sato, Tsukasa Oikawa, Yasuhito Onodera, Jin-Min Nam, Ari Hashimoto, Kiyoshi Fukunaga, Kanako C. Hatanaka, Yutaka Hatanaka, Yoshihiro Matsuno, Satoshi Fukuda, Hisataka Sabe
CELL COMMUNICATION AND SIGNALING, 14, 1, 28, Nov. 2016, [Peer-reviewed]
English, Scientific journal - ZEB1 induces EPB41L5 in the cancer mesenchymal program that drives ARF6-based invasion, metastasis and drug resistance
A. Hashimoto, S. Hashimoto, H. Sugino, A. Yoshikawa, Y. Onodera, H. Handa, T. Oikawa, H. Sabe
ONCOGENESIS, 5, 9, e259, Sep. 2016, [Peer-reviewed]
English, Scientific journal - Tumor responsiveness to statins requires overexpression of the ARF6 pathway.
Sabe H, Hashimoto A, Hashimoto S, Oikawa T
Molecular & cellular oncology, 3, 4, e1185564, Jul. 2016, [Peer-reviewed], [International Magazine]
English, Scientific journal, The mevalonate pathway results in the prenylation of small GTPases, which are pivotal for oncogenesis and cancer malignancies. However, inhibitors of this pathway, such as statins, have not necessarily produced favorable results in clinical trials. We recently identified properties of statin responders, together with the underlying molecular mechanisms and simple biomarkers to predict these responders. - P53-and mevalonate pathway-driven malignancies require Arf6 for metastasis and drug resistance
Ari Hashimoto, Tsukasa Oikawa, Shigeru Hashimoto, Hirokazu Sugino, Ayumu Yoshikawa, Yutaro Otsuka, Haruka Handa, Yasuhito Onodera, Jin-Min Nam, Chitose Oneyama, Masato Okada, Mitsunori Fukuda, Hisataka Sabe
JOURNAL OF CELL BIOLOGY, 213, 1, 81, 95, Apr. 2016, [Peer-reviewed]
English, Scientific journal - Lysophosphatidic acid activates Arf6 to promote the mesenchymal malignancy of renal cancer
Shigeru Hashimoto, Shuji Mikami, Hirokazu Sugino, Ayumu Yoshikawa, Ari Hashimoto, Yasuhito Onodera, Shotaro Furukawa, Haruka Handa, Tsukasa Oikawa, Yasunori Okada, Mototsugu Oya, Hisataka Sabe
NATURE COMMUNICATIONS, 7, 10656, Feb. 2016, [Peer-reviewed]
English, Scientific journal - A Novel Phthalimide Derivative, TC11, Has Preclinical Effects on High-Risk Myeloma Cells and Osteoclasts
Maiko Matsushita, Yoshie Ozaki, Yuka Hasegawa, Fukiko Terada, Noriko Tabata, Hirokazu Shiheido, Hiroshi Yanagawa, Tsukasa Oikawa, Koichi Matsuo, Wenlin Du, Taketo Yamada, Masashi Hozumi, Daiju Ichikawa, Yutaka Hattori
PLOS ONE, 10, 1, e0116135, Jan. 2015, [Peer-reviewed]
English, Scientific journal - Regulation of osteoclasts by membrane-derived lipid mediators
Tsukasa Oikawa, Yukiko Kuroda, Koichi Matsuo
CELLULAR AND MOLECULAR LIFE SCIENCES, 70, 18, 3341, 3353, Sep. 2013, [Peer-reviewed], [Lead author, Corresponding author]
English, 10748382 - Acquired expression of NFATc1 downregulates e-cadherin and promotes cancer cell invasion
Tsukasa Oikawa, Atsuko Nakamura, Nobuyuki Onishi, Taketo Yamada, Koichi Matsuo, Hideyuki Saya
Cancer Research, 73, 16, 5100, 5109, 16, 15 Aug. 2013, [Peer-reviewed], [Lead author, Corresponding author]
English, Scientific journal, 10748382 - IRSp53 Mediates Podosome Formation via VASP in NIH-Src Cells
Tsukasa Oikawa, Hitomi Okamura, Franziska Dietrich, Yosuke Senju, Tadaomi Takenawa, Shiro Suetsugu
PLOS ONE, 8, 3, e60528, Mar. 2013, [Peer-reviewed], [Lead author]
English, Scientific journal - Possible role of IRTKS in Tks5-Driven osteoclast fusion
Tsukasa Oikawa, Koichi Matsuo
Communicative and Integrative Biology, 5, 5, 511, 515, 5, Sep. 2012, [Peer-reviewed], [Lead author, Corresponding author]
English, Scientific journal, 10748382 - Tks5-dependent formation of circumferential podosomes/invadopodia mediates cell-cell fusion
Tsukasa Oikawa, Masaaki Oyama, Hiroko Kozuka-Hata, Shunsuke Uehara, Nobuyuki Udagawa, Hideyuki Saya, Koichi Matsuo
JOURNAL OF CELL BIOLOGY, 197, 4, 553, 568, May 2012, [Peer-reviewed], [Lead author, Corresponding author]
English, Scientific journal, 10748382 - Membrane lipids in invadopodia and podosomes: Key structures for cancer invasion and metastasis
Hideki Yamaguchi, Tsukasa Oikawa
ONCOTARGET, 1, 5, 320, 328, Sep. 2010, [Peer-reviewed]
English - PtdIns(3,4)P2 instigates focal adhesions to generate podosomes
Tsukasa Oikawa, Tadaomi Takenawa
CELL ADHESION & MIGRATION, 3, 2, 195, 197, Apr. 2009, [Peer-reviewed], [Lead author]
English, Scientific journal, 10748383 - Sequential signals toward podosome formation in NIH-src cells
Tsukasa Oikawa, Toshiki Itoh, Tadaomi Takenawa
JOURNAL OF CELL BIOLOGY, 182, 1, 157, 169, Jul. 2008, [Peer-reviewed], [Lead author]
English, Scientific journal, 10748383 - Rac-WAVE-mediated actin reorganization is required for organization and maintenance of cell-cell adhesion
Daisuke Yamazaki, Tsukasa Oikawa, Tadaomi Takenawa
JOURNAL OF CELL SCIENCE, 120, 1, 86, 100, Jan. 2007, [Peer-reviewed]
English, Scientific journal - The RAC binding domain/IRSp53-MIM homology domain of IRSp53 induces RAC-dependent membrane deformation
Shiro Suetsugu, Kazutaka Murayama, Ayako Sakamoto, Kyoko Hanawa-Suetsugu, Azusa Seto, Tsukasa Oikawa, Chiemi Mishima, Mikako Shirouzu, Tadaomi Takenawa, Shigeyuki Yokoyama
JOURNAL OF BIOLOGICAL CHEMISTRY, 281, 46, 35347, 35358, Nov. 2006, [Peer-reviewed]
English, Scientific journal - Optimization of WAVE2 complex-induced actin polymerization by membrane-bound IRSp53, PIP3, and Rac
S Suetsugu, S Kurisu, T Oikawa, D Yamazaki, A Oda, T Takenawa
JOURNAL OF CELL BIOLOGY, 173, 4, 571, 585, May 2006, [Peer-reviewed]
English, Scientific journal - Coordination between the actin cytoskeleton and membrane deformation by a novel membrane tubulation domain of PCH proteins is involved in endocytosis
K Tsujita, S Suetsugu, N Sasaki, M Furutani, T Oikawa, T Takenawa
JOURNAL OF CELL BIOLOGY, 172, 2, 269, 279, Jan. 2006, [Peer-reviewed]
English, Scientific journal - PtdIns(3,4,5)P-3 binding is necessary for WAVE2-induced formation of lamellipodia
T Oikawa, H Yamaguchi, T Itoh, M Kato, T Ijuin, D Yamazaki, S Suetsugu, T Takenawa
NATURE CELL BIOLOGY, 6, 5, 420, +, May 2004, [Peer-reviewed], [Lead author]
English, Scientific journal, 27679174
Other Activities and Achievements
- Macroscopic order formation in myoblast populations driven by intracellular molecular dynamics
麓佳月, 高田真吾, 小野寺康仁, 川口喬吾, 畠山鎮次, 佐邊壽孝, 及川司, 日本分子生物学会年会プログラム・要旨集(Web), 45th, 2022 - p53 counteracts EZH2 at the nuclear lamina to prevent H3K27 hypermethylation
及川司, 大西なおみ, 小野寺康仁, 橋本あり, 植田幸嗣, 佐邊壽孝, 日本生化学会大会(Web), 93rd, 2020 - 膵癌ドライバー変異はmRNA翻訳と蛋白質プレニル化を介しARF6が駆動する癌免疫回避を促進する(Pancreatic KRAS/TP53 mutations promote ARF6-based immune evasion via activating mRNA translation and protein prenylation)
橋本 あり, 橋本 茂, 古川 聖太郎, 蔦保 暁生, 小野寺 康人, 半田 悠, 及川 司, 水上 裕輔, 西川 義浩, 児玉 裕三, 村上 正晃, 平野 聡, 佐邊 壽孝, 日本癌学会総会記事, 78回, P, 3033, Sep. 2019
日本癌学会, English - Requirement for p53 in intra-nuclear dynamics of the K27-trimethylated histone H3 during DNA replication
及川司, 大西なおみ, 小野寺康仁, 橋本あり, 植田幸嗣, 佐邊壽孝, 日本生化学会大会(Web), 92nd, 2019 - 膵癌ドライバー変異はARF6-AMAP1経路を活性化し悪性度と免疫回避能を促進する(Pancreatic KRAS and TP53 oncogenes cooperatively activate ARF6-AMAP1 pathway to drive malignancy and immune evasion)
橋本 あり, 橋本 茂, 古川 聖太郎, 蔦保 暁生, 小野寺 康仁, 大塚 勇太郎, 半田 悠, 及川 司, 水上 裕輔, 村上 正晃, 平野 聡, 佐邊 壽孝, 日本癌学会総会記事, 77回, 2219, 2219, Sep. 2018
日本癌学会, English - 上皮細胞においてp53はE-cadherin遺伝子発現制御部位に結合し、EZH2による発現抑制に拮抗する
及川 司, 大塚 勇太郎, 小野寺 康仁, 堀川 芽衣, 橋本 あり, 橋本 茂, 鈴木 穣, 佐邊 壽孝, 生命科学系学会合同年次大会, 2017年度, [3PT18, 06(3P, Dec. 2017
生命科学系学会合同年次大会運営事務局, English - 膵癌ドライバー変異はARF6経路を介して癌悪性度とPD‐L1発現を促進する
橋本あり, 橋本茂, 古川聖太郎, 古川聖太郎, 蔦保暁生, 蔦保暁生, 大塚勇太郎, 半田悠, 小野寺康仁, 及川司, 平野聡, 佐邊壽孝, 日本生化学会大会(Web), 90th, ROMBUNNO.1P‐1028 (WEB ONLY), 1028], Dec. 2017
生命科学系学会合同年次大会運営事務局, Japanese - がんの浸潤・転移研究の新機軸 Arf6経路 難治性癌の悪性度進展・抗癌剤抵抗性に根幹的経路
佐邊 壽孝, 橋本 あり, 小野寺 康仁, 及川 司, 橋本 茂, 日本癌学会総会記事, 76回, S1, 2, Sep. 2017
日本癌学会, English - 上皮形質安定性をp53に依存する上皮細胞と依存しない上皮細胞の差異に関する解析
及川 司, 大塚 勇太郎, 小野寺 康仁, 堀川 芽衣, 橋本 あり, 橋本 茂, 鈴木 穣, 佐邊 壽孝, 日本癌学会総会記事, 76回, P, 1107, Sep. 2017
日本癌学会, English - 好中球のケモタキシスにおいて,ARF1の活性化は,ARF1‐RAC1の相互制御回路を開始する
真崎雄一, 小野寺康仁, 東恒仁, 堀之内孝広, 及川司, 佐邊壽孝, 日本細胞生物学会大会(Web), 69th, ROMBUNNO.T8‐11(P1‐077) (WEB ONLY), 63, May 2017
(一社)日本細胞生物学会, Japanese - p53はEZH2と機能的に競合することで上皮性維持に寄与する
及川 司, 大塚 勇太郎, 小野寺 康仁, 半田 悠, 橋本 あり, 橋本 茂, 鈴木 穣, 佐邊 壽孝, 日本癌学会総会記事, 75回, J, 3030, Oct. 2016
日本癌学会, English - メバロン酸経路阻害剤スタチンはArf6経路を高発現する癌に有効である
橋本 あり, 橋本 茂, 及川 司, 大塚 勇太郎, 半田 悠, 小野寺 康仁, 佐邊 壽孝, 日本生化学会大会プログラム・講演要旨集, 89回, [1P, 268], Sep. 2016
(公社)日本生化学会, Japanese - 膵癌細胞の浸潤・転移および化学療法抵抗性メカニズムの解明
古川 聖太郎, 橋本 あり, 橋本 茂, 小野寺 康仁, 及川 司, 大塚 勇太郎, 佐邊 壽孝, 平野 聡, 日本外科学会定期学術集会抄録集, 116回, PS, 002, Apr. 2016
(一社)日本外科学会, Japanese - p53はエピジェネティック制御を介して上皮性を維持する
及川 司, 小野寺 康仁, 大塚 勇太郎, 半田 悠, 橋本 あり, 橋本 茂, 鈴木 穣, 佐邊 壽孝, 日本生化学会大会・日本分子生物学会年会合同大会講演要旨集, 88回・38回, [2P1108], [2P1108], Dec. 2015
(公社)日本生化学会, English - Arf6-AMAP1経路によるROS制御は乳癌の放射線抵抗性に寄与する
小野寺 康仁, 南 ジンミン, 及川 司, 白土 博樹, 佐邊 壽孝, 日本癌学会総会記事, 74回, E, 1049, Oct. 2015
日本癌学会, English - Arf6-AMAP1経路によるROS制御は乳癌の放射線抵抗性に寄与する
小野寺 康仁, 南 ジンミン, 及川 司, 白土 博樹, 佐邊 壽孝, 日本癌学会総会記事, 74回, E, 1049, Oct. 2015
日本癌学会, English - Arf6-AMAP1経路による酸化還元状態の恒常性維持は乳癌の放射線抵抗性に寄与する(Robust redox homeostasis mediated by Arf6-AMAP1 pathway confers resistance to ionizing radiation in breast cancer)
小野寺 康仁, 南 ジンミン, 及川 司, 白土 博樹, 佐邊 壽孝, 日本癌学会総会記事, 73回, E, 3010, Sep. 2014
日本癌学会, English - EZH2発現亢進により創出されるArf6を中心とした間葉浸潤に特化した分子装置は腎癌の予後不良に関与する(EZH2 generates Arf6-based mesenchymal invasion machinery that is central to poor prognosis of renal cancer)
橋本 茂, 杉野 弘和, 橋本 あり, 吉河 歩, 及川 司, 半田 悠, 大家 基嗣, 三上 修治, 佐邊 壽孝, 日本癌学会総会記事, 73回, J, 2075, Sep. 2014
日本癌学会, English - 乳癌において変異p53がリガンド反応性の間葉型浸潤分子装置を創出する機序(TP53 alterations generate Arf6-based mesenchymal invasion pathway that is activated by RTKs and TGFβ1 in breast cancer)
橋本 あり, 橋本 茂, 杉野 弘和, 吉河 歩, 及川 司, 小野寺 康仁, 半田 悠, 大塚 勇太郎, 岩見 昴亮, 小根山 千歳, 岡田 雅人, 福田 光則, 佐邊 壽孝, 日本癌学会総会記事, 73回, J, 2077, Sep. 2014
日本癌学会, English - p53は間葉系形質を持つ乳がん細胞に上皮系形質を再獲得させる(p53 recalls epithelial memory in mammary cancer cells with mesenchymal phenotypes)
及川 司, 小野寺 康仁, 橋本 あり, 橋本 茂, 佐邊 壽孝, 日本癌学会総会記事, 73回, P, 1159, Sep. 2014
日本癌学会, English - 癌放射線治療への分子生物学的アプローチ 変異p53が放射線抵抗性に根幹的な間葉型浸潤経路を創出する機構(Toward the improvement of radiotherapy: Approaches from the molecular biological point of view Mechanisms by which oncogenic mutant-p53 generates mesenchymal invasive pathway pivotal to a radiation resis
佐邊 壽孝, 橋本 あり, 橋本 茂, 小野寺 康仁, 及川 司, Nam Jin-Min, 小根山 千歳, 杉野 弘和, 吉河 歩, 大塚 勇太郎, 半田 悠, 芳野 正修, 岡田 雅人, 日本癌学会総会記事, 72回, 64, 64, Oct. 2013
日本癌学会, English - アクチン細胞骨格による新たな細胞機能と生体機能の制御 アダプター分子Tks5依存的なポドソーム/インベードポディア形成と、これを介した破骨/がん細胞融合の解析
及川 司, 尾山 大明, 秦 裕子, 中村 敦子, 大西 伸幸, 上原 俊介, 宇田川 信之, 山田 健人, 佐谷 秀行, 松尾 光一, 日本生化学会大会プログラム・講演要旨集, 86回, 1S16a, 3, Sep. 2013
(公社)日本生化学会, Japanese - アダプター分子Tks5依存的なポドソーム/インベードポディア形成と,これを介した破骨/がん細胞融合の解析
及川司, 尾山大明, 秦裕子, 中村敦子, 大西伸幸, 上原俊介, 宇田川信之, 山田健人, 佐谷秀行, 松尾光一, 日本生化学会大会(Web), 86th, 1S16A-3 (WEB ONLY), 3, 2013
(公社)日本生化学会, Japanese - ポドソーム形成と細胞融合におけるアダプター分子Tks5の機能解析(Tks5-dependent formation of circumferential podosomes mediates cell-cell fusion)
及川 司, 松本歯学, 37, 2-3, 186, 186, Dec. 2011
松本歯科大学学会, English - Tks5によるポドソーム形成と破骨細胞融合メカニズム
及川 司, 尾山 大明, 秦 裕子, 佐谷 秀行, 松尾 光一, 日本骨代謝学会学術集会プログラム抄録集, 29回, 241, 241, Jul. 2011
(一社)日本骨代謝学会, English - ポドソーム形成と細胞融合におけるアダプター分子Tks5の機能解析(Tks5-dependent formation of circumferential podosome mediates cell-cell fusion)
及川 司, 尾山 大明, 秦 裕子, 佐谷 秀行, 松尾 光一, 日本細胞生物学会大会講演要旨集, 63回, 144, 144, May 2011
(一社)日本細胞生物学会, English - 破骨細胞融合におけるアダプター分子Tks5の機能解析
及川 司, 松尾 光一, 日本骨代謝学会学術集会プログラム抄録集, 28回, 260, 260, Jul. 2010
(一社)日本骨代謝学会, English - 細胞接着・ECM・細胞間相互作用 破骨細胞融合におけるアダプター分子Tks5の機能解析(Cell adhesion, ECM and cell-cell interaction Tks5 is required for the cell-cell fusion process of osteoclastogenesis)
及川 司, 佐谷 秀行, 松尾 光一, 日本細胞生物学会大会講演要旨集, 62回, 121, 121, May 2010
(一社)日本細胞生物学会, English - (あり方委員会企画)Bone Cell Topology 破骨細胞と骨芽細胞の極性決定
及川 司, 松尾 光一, 日本骨代謝学会学術集会プログラム抄録集, 27回, 118, 118, Jul. 2009
(一社)日本骨代謝学会, Japanese - 癌浸潤転移における細胞運動のメカニズム 浸潤突起形成の分子メカニズム(Molecular mechanisms of cell migration in cancer invasion and metastasis Sequential signals toward podosome formation in NIH-src cells)
及川 司, 伊藤 俊樹, 竹縄 忠臣, 日本細胞生物学会大会講演要旨集, 60回, 94, 94, Jun. 2008
(一社)日本細胞生物学会, English - 浸潤突起形成の分子メカニズム(Sequential signals toward podosome formation in NIH-src cells)
及川 司, 伊藤 俊樹, 竹縄 忠臣, 日本細胞生物学会大会講演要旨集, 60回, 166, 166, Jun. 2008
(一社)日本細胞生物学会, English - WASP/WAVE蛋白質はがん細胞の運動や浸潤に関与する(Cancer and Failures in Cell Polaritv Regulation WASP/WAVE proteins regulate the migration and invasion of cancer cells)
竹縄 忠臣, 及川 司, 末次 志郎, 日本癌学会総会記事, 66回, 68, 68, Aug. 2007
日本癌学会, English - PI3Kおよび関連シグナル伝達分子の機能 癌細胞におけるD3-ホスホイノシチドの定量化と視覚化のためのホスホイノシチド結合ドメインの利用(Use of phosphoinositide-binding domains for the quantification and visualization of D3-phosphoinositides in cancer cells)
伊藤 俊樹, 及川 司, 辻田 和也, 竹縄 忠臣, 日本発生生物学会・日本細胞生物学会合同大会要旨集, 40回・59回, 15, 15, May 2007
日本発生生物学会・日本細胞生物学会, English - Tks5/FISHはPtdIns(3,4)P2とPtdIns(3,4,5)P3が豊富な局所接着部(focal adhesion)へ自己分子を局在化させることによりpodosome形成を開始させる(Tks5/FISH initiates podosome formation by localizing itself to PtdIns(3,4)P2- and PtdIns(3,4,5)P3-enriched focal adhesions)
及川 司, 伊藤 俊樹, 竹縄 忠臣, 日本発生生物学会・日本細胞生物学会合同大会要旨集, 40回・59回, 131, 131, May 2007
日本発生生物学会・日本細胞生物学会, English - 分子標的としてのシグナル伝達系 N-WASP/WAVEのシグナルと癌浸潤、転移
竹縄 忠臣, 末次 志郎, 山崎 大輔, 及川 司, 栗栖 修作, 日本癌学会総会記事, 65回, 433, 433, Sep. 2006
日本癌学会, Japanese - 【形と運動を司る細胞のダイナミクス 最新技術による分子機構の解明から疾患治療への展開まで】 細胞と形態形成・疾患 癌の浸潤,転移とアクチン細胞骨格による浸潤突起形成
及川 司, 実験医学, 24, 13, 2063, 2068, Aug. 2006
(株)羊土社, Japanese - Sigualing of cell migration
Takenawa T, Suetsugu S, Oikawa T, Biophysics, 43, 1, S8, S8, 25 Aug. 2003
一般社団法人日本生物物理学会, Japanese - Racによるlamellipodia形成におけるWAVE2とPtdIns(3,4,5)P3の関わり
及川 司, 末次 志郎, 伊藤 俊樹, 山口 英樹, 竹縄 忠臣, 日本細胞生物学会大会講演要旨集, 56回, 23, 23, May 2003
(一社)日本細胞生物学会, Japanese - Recによるlamellipodia形成におけるWAVE2とPtdIns(3,4,5)P3の関わり
及川司, 末次志郎, 伊藤俊樹, 山口英樹, 竹縄忠臣, 日本細胞生物学会大会講演要旨集, 56th, 23, 2003
Japanese
Research Themes
- Regulatory mechanisms of histone modification by nuclear envelope integrity
Grants-in-Aid for Scientific Research
Apr. 2024 - Mar. 2027
及川 司
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Hokkaido University, 24K09447 - Osteoclast fusion mechanism based on plasma membrane curvature and tension
Grants-in-Aid for Scientific Research
01 Apr. 2022 - 31 Mar. 2025
伊藤 俊樹, 及川 司
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (B), Kobe University, 22H02574 - Molecular mechanism of the p53-mediated intra-nuclear dynamics of H3K27me3
Grants-in-Aid for Scientific Research
01 Apr. 2020 - 31 Mar. 2023
及川 司
本研究は、DNA複製期のヒストンH3と相互作用するタンパク質群(インタラクトーム)において、癌抑制遺伝子産物p53が、抑制性ヒストン修飾H3K27me3化を担う分子EZH2を排除する、という申請者らの新しい知見に焦点を当て、その分子的基盤とともに、細胞の上皮性維持への寄与を明らかにすることを目的としている。
本年度は、p53が存在する時にH3のインタラクトームに含まれる量が大きく増加する分子、CTDNEP1及び、その脱リン酸化基質分子の一つでありフォスファチジン酸(PA)からジアシルグリセロール(DAG)への変換を担うLipinの機能解析を行った。その結果、(1)CTDNEP1は核膜及び小胞体様の細胞内構造に局在すること、(2)CTDNEP1の発現はp53の存在によりタンパクレベルで安定化されること、(3)CTDNEP1の発現抑制は、p53の発現抑制と同様にH3K27me3の核膜近傍領域への異所性蓄積を引き起こすこと、(4)核内に存在するLipinタンパク量はp53やCTDNEP1に依存すること、(5)p53やCTDNEP1は核内PA量の調節に関与することを細胞核脂質の質量分析から明らかにした。これらのことから、p53が存在することでCTDNEP1が核膜において安定化し、Lipinは脱リン酸化されて活性化し、核膜の脂質組成がPAからDAGに富んだ状態になることが示唆された。ヒストンH3はDAGよりもPAに強く結合することを考え合わせると、上記のp53-CTDNEP1-Lipinによる核内PA量の低下が行われない状況では、DNA複製に伴い細胞質から核内へ一斉に輸送されるヒストンH3.1が核膜付近に蓄積し、これが異所性H3K27me3の原因となり得るのではないかと考えられた。
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Hokkaido University, 20K07305 - Regulation of epithelial integrity through the nonequilibrium dynamics of the histone methylation during replication
Grants-in-Aid for Scientific Research
01 Apr. 2020 - 31 Mar. 2022
及川 司
遺伝子発現に関わるヒストン修飾は、細胞内代謝産物によって動的に制御されているが、ヌクレオソーム構造の再編成を伴うDNA複製時、娘鎖においてヒストンの化学修飾状態が維持または変化する機構は良くわかっていない。申請者らは、転写抑制性メチル化ヒストン修飾(K27-trimethylated histone H3: H3K27me3)のゲノム上におけるパターンがDNA複製を経ても安定に維持されるにあたり、がん抑制遺伝子産物p53が重要な役割を果たすことを見出した。p53が存在しない時、DNA複製期に細胞質から核内へ輸送される新規未修飾ヒストンH3.1が、核膜に一時的に蓄積し、ここで異所性にH3K27me3化された。このH3K27me3化には、核膜近傍領域においてPRC2タンパク複合体の触媒サブユニットであるEZH2とH3との分子近接が観察された。従って、娘鎖において少なくとも一部のゲノム領域で、新規未修飾ヒストンH3が供給される代わりに、H3K27me3が供給されると考えられる。この系を用い、DNA複製部位において新規未修飾ヒストンH3の供給量が減少し、代わりにH3K27me3が供給されたとき、娘鎖においてメチル化ヒストンパターン(H3K27me3, H3K4me3)がどのように遷移するか、理論解析を進めた。その結果、DNA複製部位への未修飾新規ヒストンの流入量、あるいはメチル基ドナーであるSAMの供給量が過剰であるなど、平衡から遠く離れた時、メチル化ヒストンのわずかな初期濃度差(擾乱)が増幅し、ある複製回数以降から不可逆的に隔たるというシミュレーション結果を得た。これを上記のp53喪失の系で検証したところ、p53を喪失した上皮細胞においては、既にH3K27me3化されているゲノム領域(PRC2標的領域)でH3K27me3量の増加が観察された。
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area), Hokkaido University, 20H05523 - Analysis of the mechanisms by which intra-tumor metabolic microenvironment leads to radioresistance
Grants-in-Aid for Scientific Research
01 Apr. 2018 - 31 Mar. 2021
Onodera Yasuhito
Using cell-specific regulation of glucose metabolism, we co-cultured glucose-sufficient and glucose-deficient cancer cells and established "metabolic cooperation" between them to analyze viability, intracellular metabolism, phenotypic changes, and response to radiation. The above experimental system revealed that cancer cells in a glucose-depleted state maintain their viability by obtaining metabolites from glucose-sufficient cells, and that oxidative stress and ER stress in the former cells are markedly suppressed. Estimation of the mediating substances and mechanisms, as well as the various phenotypic changes that occur in the metabolic cooperative state, are currently under analysis.
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (B), Hokkaido University, 18H02759 - Epigenetic regulation of the epithelial integrity by p53
Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
01 Apr. 2016 - 31 Mar. 2019
Oikawa Tsukasa
Analyses of various cancer cells have demonstrated a statistical correlation between TP53 mutations and the infringement of epithelial phenotypes, suggesting that some epithelial cells require TP53 to maintain their integrity. Likewise, the ENCODE project indicates the enrichment of putative p53 binding motifs within the regulatory regions of epithelial genes. However, the roles of p53 in epithelial integrity still largely remain elusive. We showed that epithelial genes may require normal-p53 to encounter EZH2. The loss of normal-p53 induced EZH2-mediated H3K27me3 deposition at histones regulating epithelial genes, such as CDH1. p53 can access this locus in epithelial cells but not in mesenchymal cells. Our results in vitro and from TCGA datasets indicated that H3K27me3 deposition by the loss of p53 is specific to epithelial genes. Our results identified an uncharted function of normal-p53 to protect epithelial genes from EZH2-mediated repression to maintain epithelial integrity.
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Hokkaido University, 16K08569 - A new role of podosome formation as a mediator of cell-cell fusion
Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (A)
01 Apr. 2011 - 31 Mar. 2014
OIKAWA Tsukasa
Cell-cell fusion requires dynamic rearrangement of the plasma membrane and cytoskeleton, and this process involves numerous previously characterized factors. However, the mechanisms and consequences of cell-cell fusion remains obscure. This study revealed that an adaptor protein Tks5 is essential for both formation of circumferential podosomes and osteoclast fusion without altering osteoclast differentiation. As Tks5 is known to promote the formation of invadopodia in cancer cells, I tested if these cells also have the potential to fuse with osteoclasts. Among the cells tested, B16F0 melanoma cells formed circumferential invadopodia with Tks5 accumulation. Co-culture of B16F0 melanoma cells with osteoclasts in an inflammatory milieu promoted increased formation of melanoma-osteoclast hybrid cells. These results revealed a previously unknown mechanism of regulation of both circumferential podosomes/invadopodia formation and cell-cell fusion by Tks5.
Japan Society for the Promotion of Science, Grant-in-Aid for Young Scientists (A), 慶應義塾大学, Principal investigator, Competitive research funding, 23689020 - In vivo analysis of cell polarity during cell-cell fusion
Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research
2011 - 2013
OIKAWA Tsukasa
Among various phosphatidylinositols (PI) on the plasma membrane, the most abundant product, PI(4,5)P2 and locally-produced PI(3,4,5)P3 and PI(3,4)P2 seem to be particularly important in polarity formation of the cells. The PH domain of PLC delta1 binds to PI(4,5)P2 while the PH domain of Akt binds to PI(3,4)P2 and PI(3,4,5)P3, which is locally produced depending on PI3-kinase activity. By using these domains, I succeeded in observing the polarity of fusing cells. To apply this system in vivo, KH2 ES cells which can express those domains fused to GFP or RFP in response to doxycyclin were generated. Now that genetic quality of the ES cells were confirmed, the mice who express the polarity probe is being generated.
Japan Society for the Promotion of Science, Grant-in-Aid for Challenging Exploratory Research, 慶應義塾大学, Principal investigator, Competitive research funding, 23659162 - Molecular Mechanisms of podosome formation
Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)
2008 - 2009
OIKAWA Tsukasa
The great majority of cancers occur in epithelial tissues, yielding carcinomas. Given that epithelial cells are on the basement membrane underneath, they must degrade it to travel to distant sites. To initiate the invasion process, they must make contact with the extracellular matrices (ECM). Thus, the cell-matrix interactions must be one of the triggers that allow cancer cells to invade. To penetrate into the ECM, actin-rich adhesion structures called invadopodia or podosomes is thought to play pivotal roles for degrading it. I have studied the mechanism of invadopodium/podosome formation in Src-transformed NIH3T3 cells. In this study, based on the results of RNAi, identification of binding proteins by mass spectrometry, protein interaction and live-cell imaging analysis, I have established a stepwise mechanism for invadopodium formation. Invadopodia initiate from focal adhesions (FAs) due to changes in the phosphorylation status of proteins and in the composition of phosphoinositides on the plasma membrane. The onset of actin polymerization is triggered by PI(3,4)P2 production and Tks5 recruitment followed by N-WASP accumulation. This step involves intricate interactions of Tks5 with both PI(3,4)P2 and Grb2 at FAs
Japan Society for the Promotion of Science, Grant-in-Aid for Young Scientists (B), Keio University, Principal investigator, Competitive research funding, 20790255 - 細胞骨格調節タンパクとこれの時・空間制御因子としての脂質シグナルの解析
科学研究費助成事業 特別研究員奨励費
2005 - 2006
及川 司
近年、粘菌や好中球から繊維芽細胞にいたる様々な細胞の方向性を持った遊走が、走化性因子のわずかな勾配を感じて活性化されたPI3-キナーゼとその産物のひとつ、PIP3から始まるシグナルによって起こることが分かってきている。一方でGFPを融合させたAktのPHドメインを用いてPIP3の局在を可視化すると、この脂質は遊走細胞の先端に局所的に産生されていることが明らかになり、イノシトールリン脂質が細胞の極性や遊走に積極的に関与していることが明らかになっている。研究代表者はこれまで細胞の移動先端部で活性化され、アクチン重合を促進し細胞に駆動力を与えるWASPファミリータンパク質のひとつ、WAVE2がいかにして活性化されるのかということを解く過程で、イノシトールリン脂質との結合を見出した。本研究ではイノシトールリン脂質結合の性質を明らかにし、邸WASPによる浸潤突起形成やWA〜Eによる葉状仮足形成、及び方向性を持った細胞遊走へのイノシトールリン脂質の関与を解明することを目的としている。浸潤能の高いがん細胞に多く見られる浸潤斑と呼ばれる浸潤突起は、N-WASPがその骨格であるアクチン重合において主要な役割を果たしている。一方、様々なイノシトールリン脂質結合ドメインを用いて細胞内のイノシトールリン脂質の局在を可視化したところ、PI(3,4)P2が浸潤斑に強く極性を持って局在していた。リボソーム法やDot Blot法により、各種イノシトールリン脂質とN-WASPとの結合特異性を検証したところ、NLWASPは特定のイノシトールリン脂質とは強く結合しなかった。一方、N-WASPとともに浸潤斑に局在するアダプタータンパク質、Tks5/FISHはN-WASPやdynaminと結合し、さらにいくつかのイノシトールリン脂質とも結合することがわかった。これらのことから、N-WASPはその結合タンパク質であるTks5/FISHと協調してイノシトールリン脂質による制御を受けていることが示唆された。またRNAiによるTks5/FISHやN-WASPの発現抑制実験から、浸潤突起ができるメカニズムとして、(1)focal adhesionにおけるPI(3,4)P2やPI(3,4,5)P3の集積、(2)Tks5/FISHとN-WASPを含む複合体の集積、(3)N-WASPによるアクチン重合、という時間、空間制御が行われていることが示唆された。
日本学術振興会, 特別研究員奨励費, 東京大学, 05J11594
