Faculty Profiles - TOKUMITSU Hiroshi

MISC - TOKUMITSU Hiroshi

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CaMKKの基質認識機構の解明と特異的阻害分子開発への応用

川俣一晟, 美馬光志, 山内陽生, 北前勝哉, 山内香奈, 大塚里美, 曲正樹, 金山直樹, 徳光浩

日本生化学会大会(Web) 95th 2022

CaMKK阻害剤(TIM-063)を用いた阻害剤プロテオミクス解析

大塚里美, 波多野直哉, 奥村太晟, 澤直樹, 田邊史子, 傳田美和子, 金山直樹, 曲正樹, 森下了, 石川彰彦, 徳光浩

日本生化学会大会(Web) 94th 2021

新規S100A6標的分子(HMG20A)の同定と相互作用解析

山本真穂, 近藤里奈, 傳田美和子, 土居青太, 金山直樹, 曲正樹, 森下了, 徳光浩

日本生化学会大会(Web) 92nd 2019

筋肉特異的Calmodulin結合分子,Striated Muscle Activator of Rho Signaling(STARS)の分子間相互作用解析

赤木魁, 田中啓之, 金山直樹, 曲正樹, 波多野直哉, 徳光浩

日本分子生物学会年会プログラム・要旨集(Web) 42nd 2019

CaMKKβのリン酸化/脱リン酸化による動的制御機構の解明

高畠翔太, 福本侑世, 金山直樹, 曲正樹, 波多野直哉, 徳光浩

日本分子生物学会年会プログラム・要旨集(Web) 42nd 2019

Ca²⁺/calmodulin-dependent protein kinase kinase—カルシウムシグナル伝達から創薬へ— Reviewed

Hiroshi Tokumitsu

Journal of Japanese Biochemical Society 90 ( 4 ) 452 - 461 2018.8

インターラクトーム解析法を用いたヒトS100A6標的分子の探索

坂根恭平, 西口みゆ, 古谷雄穂, 傳田美和子, 山口文徳, 曲正樹, 金山直樹, 森下了, 徳光浩

日本生化学会大会(Web) 88th 1P0204 (WEB ONLY) - [1P0204] 2015.12

Ca²⁺/Calmodulin結合型転写因子の網羅的同定

太尾田泰成, 大西和貴, 古谷雄穂, 傳田美和子, 金山直樹, 曲正樹, 森下了, 徳光浩

日本生化学会大会(Web) 88th 3P0185 (WEB ONLY) - [3P0185] 2015

ヒトCalmodulin標的分子の網羅的同定

古谷雄穂, 西口みゆ, 傳田美和子, 曲正樹, 金山直樹, 森下了, 徳光浩

日本生化学会大会(Web) 87th 4T14A-01(3P-324) (WEB ONLY) - 01] 2014.10

S 100 PROTEINS MODULATE PROTEIN PHOSPHATASE 5 FUNCTION : A LINK BETWEEN Ca2+ SIGNAL TRANSDUCTION AND PROTEIN DEPHOSPHORYLATION

Fuminori Yamaguchi, Yoshinori Umeda, Seiko Shimamoto, Mitsumasa Tsuchiya, Hiroshi Tokumitsu, Masaaki Tokuda, Ryoji Kobayashi

JOURNAL OF PHYSIOLOGICAL SCIENCES 63 S139 - S139 2013

[Small-molecule modulator of calcium signaling]. Reviewed

Kobayashi R, Tokumitsu H, Fujimoto T

Nihon rinsho. Japanese journal of clinical medicine 70 Suppl 8 277 - 280 2012.11

CaMKKの自己リン酸化による活性調節メカニズム

徳光浩, 横倉沙紀, 本, 波多野直哉, 藤本智仁, 小林良二

日本生化学会大会プログラム・講演要旨集 84回 3T10p - 6 2011.9

ATPアナログを用いたCaMKKの新規標的基質分子の同定

藤本智仁, 波多野直哉, 野崎直仁, 横倉沙紀, 本, 小林良二, 徳光浩

日本生化学会大会プログラム・講演要旨集 84回 3P - 0376 2011.9

新しいニューロン性カルモジュリン結合蛋白PRG-1(可塑性関連遺伝子1)(PRG-1 (plasticity related gene 1), a novel neuronal calmodulin-binding protein)

徳光浩, 波多野直哉, 土屋光正, 揺本沙紀, 藤本智仁, 小原直樹, 小林良二, 阪上洋行

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 83回・33回 3P - 0346 2010.12

Calmodulin-Kinases: Modulators of Neuronal Development and Plasticity (vol 59, pg 914, 2008)

Gary A. Wayman, Yong-Seok Lee, Hiroshi Tokumitsu, Alcino J. Silva, Thomas R. Soderling

NEURON 64 ( 4 ) 590 - 590 2009.11

Exendin-4 regulates glucokinase expression by CaMKK/CaMKIV pathway in pancreatic beta-cell line Reviewed

K. Murao, J. Li, H. Imachi, T. Muraoka, H. Masugata, G. X. Zhang, R. Kobayashi, T. Ishida, H. Tokumitsu

DIABETES OBESITY & METABOLISM 11 ( 10 ) 939 - 946 2009.10

Language：English Publisher：WILEY-BLACKWELL PUBLISHING, INC

Aim
Glucokinase (GK) in pancreatic beta cells is thought to be involved in insulin secretion and glucose homeostasis. This study investigates whether the long-acting agonist of the glucagon-like peptide 1, namely exendin-4, mediates stimulatory effects on GK gene expression through the Ca<SU2+</SU/calmodulin (CaM)-dependent protein kinase (CaMK) cascade.
Methods
GK expression was examined by real-time PCR, western blot analysis and reporter gene assay in rat insulin-secreting INS-1 cells incubated with exendin-4. CaMKIV activity was assessed by detection of activation loop phosphorylation (Thr<SU196</SU) of CaMKIV. We investigated the effect of the constitutively active form (CaMKIVc) of CaMKIV on GK promoter activity.
Results
Increased expression level of GK protein was noted in response to rising concentrations of exendin-4 with maximum induction at 10 nM. Real-time PCR analysis showed a significant increase in the amount of GK mRNA in response to rising concentrations of exendin-4. Exendin-4 also stimulated GK promoter activity but failed to do so in the presence of STO-609, a CaMKK inhibitor. This result is consistent with the observations that the upregulation of CaMKIV phosphorylation (at Thr<SU196</SU) peaked after 15 min of exposure to exendin-4 and that CaMKIVc enhanced or upregulated GK promoter activity in INS-1 cells. Furthermore, STO-609 significantly suppressed the exendin-4 - upregulated the expression of the GK protein.
Conclusion
Activation of the CaMKK/CaMKIV cascade might be required for exendin-4-induced GK gene transcription, indicating that exendin-4 plays an important role in insulin secretion in pancreatic beta cells.

DOI： 10.1111/j.1463-1326.2009.01067.x

Web of Science

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新規カルモデュリン結合タンパク質、PRG-1の同定と生化学的解析

土屋光正, 波多野直哉, 揺本沙紀, 倉, 小林良二, 阪上洋行, 徳光浩

日本生化学会大会プログラム・講演要旨集 82回 4T4a - 2 2009.9

機能的プロテオミクス法を用いたカルモデュリン結合タンパク質の網羅的探索

揺本沙紀, 横倉, 藤本智仁, 波多野直哉, 土屋光正, 中野重治, 掛川寿夫, 小林良二, 徳光浩

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 81回・31回 1T15 - 12 2008.11

Signal transduction of CaM-kinase cascade and its specific inhibitor

H Tokumitsu

JOURNAL OF PHARMACOLOGICAL SCIENCES 94 38P - 38P 2004

Neuronal calcium sensor proteins are direct targets of the insulinotropic agent repaglinide

M Okada, D Takezawa, S Tachibanaki, S Kawamura, H Tokumitsu, R Kobayashi

BIOCHEMICAL JOURNAL 375 ( 1 ) 87 - 97 2003.10

Language：English Publisher：PORTLAND PRESS

The NCS (neuronal calcium sensor) proteins, including neurocalcins, recoverins and visinin-like proteins are members of a family of Ca2+-sensitive regulators, each with three Ca2+-binding EF-hand motifs. In plants. lily CCaMK [chimaeric Ca2+/CaM (calmodulin)-dependent protein kinase] and its PpCaMK (Physcomitrella patens CCaMK) homologue are characterized by a visinin-like domain with three EF-hands. In the present study, in an effort to discover NCS antagonists. we screened a total of 43 compounds using Ca2+-dependent drug affinity chromatography and found that the insulinotropic agent repaglinide targets the NCS protein family. Repaglinide was found to bind to NCS proteins, but not to CaM or S 100 proteins, in a Ca2+-dependent manner. Furthermore. the drug antagonized the inhibitory action of recoverin in a rhodopsin kinase assay with IC50 values of 400 muM. Moreover, repaglinide tightly bound to the visinin-like domain of CCaMK and PpCaMK in a Ca2+-dependent manner and antagonized the regulatory function of the domain with IC50 values of 55 and 4 muM for CCaMK and PpCaMK respectively. Although both repaglinide and a potent insulin secretagogue, namely glibenclamide, blocked K-ATP channels with similar potency, glibenclamide had no antagonizing effect on the Ca2+-stimulated CCaMK and PpCaMK autophosphorylation, mediated by their visinin-like domain. In addition, a typical CaM antagonist, trifluoperazine, had no effect on the CCaMK and PpCaMK autophosphorylation. Repaglinide appears to be the first antagonist of NCS proteins and visinin-like domain-bearing enzymes. It may serve as a useful tool for evaluating the physiological functions of the NCS protein family. In addition, since repaglinide selectively targets NCS proteins among the EF-hand Ca2+-binding proteins, it is a potential lead compound for the development of more potent NCS antagonists.

DOI： 10.1042/BJ20030376

STO-609, a specific inhibitor of the Ca2+/calmodulin-dependent protein kinase kinase. (vol 277, pg 15813, 2002)

H Tokumitsu, H Inuzuka, Y Ishikawa, M Ikeda, Saji, I, R Kobayashi

JOURNAL OF BIOLOGICAL CHEMISTRY 278 ( 6 ) 4368 - 4368 2003.2

The Ca2+/Calmodulin-dependent Kinase Type IV is involved in the glucose-induced glucokinase transcription in INS-1 cells

Y Sayo, K Murao, S Ohtuka, H Tokumitsu, H Imachi, H Hosokawa, WM Cao, M Sato, T Ishida

DIABETES 51 A393 - A393 2002.6

新規ミオシン調節軽鎖キナーゼとして同定されたCaM‐KIの解析

水津太, 福田康朗, 上田こずえ, 菊池麻子, 村田(堀)麻希, 徳光浩, 細谷浩史

生化学 73 ( 8 ) 812 2001.8

The Ca2+/calmodulin-dependent kinase type IV is involved in the glucose-induced insulin transcription in INS-1 cells

Y Sayo, K Murao, H Tokumitsu, H Imachi, H Hosokawa, M Sato, T Ishida, J Takahara

DIABETES 49 A255 - A255 2000.5

CaM-kinase cascade in C. elegans

ETO Ko, KIMURA Yoshishige, TAKAHASHI Naomi, MURAMATSU Masa-aki, ARAI Ken-ichi, TOKUMITSU Hiroshi

21 561 - 561 1998.12

Structure and Function of CaM-kinase kinase

TOKUMITSU Hiroshi, TAKAHASHI Naomi, OSAWA Masanori, IKURA Mitsuhiko, MURAMATSU Masa-aki

21 535 - 535 1998.12

MUTAGENESIS STUDY OF CAM-KINASE-IV

H TOKUMITSU, D BRICKEY, TR SODERLING

FASEB JOURNAL 8 ( 7 ) A1224 - A1224 1994.4

CLE0, THE GM-CSF PROMOTER CIS-ACTING ELEMENT, MEDIATES INDUCTION SIGNALS IN T-CELLS AND IS RECOGNIZED BY FACTORS RELATED TO AP1 AND NF-AT

N ARAI, ES MASUDA, H TOKUMITSU, K ARAI, N ARAI

JOURNAL OF CELLULAR BIOCHEMISTRY 17 - 17 1994.1

CLEO, A COMPLEX CIS-ACTING ELEMENT REGULATING GM-CSF EXPRESSION IN T-CELLS

E MASUDA, H TOKUMITSU, A TSUBOI, Y NAITO, K ARAI, N ARAI

JOURNAL OF IMMUNOLOGY 150 ( 8 ) A51 - A51 1993.4

DIFFERENTIAL REGULATION OF LYMPHOKINE GENE INDUCTION IN TH1 AND TH2

Y NAITO, MATSUDA, I, H TOKUMITSU, ES MASUDA, A TSUBOI, RL COFFMAN, K ARAI, N ARAI

JOURNAL OF IMMUNOLOGY 150 ( 8 ) A273 - A273 1993.4

INVOLVEMENT OF REL/NF-KAPPA-B PROTEINS IN ACTIVATION OF GM-CSF GENE IN T-CELLS

A TSUBOI, ES MASUDA, H TOKUMITSU, K ARAI, N ARAI

JOURNAL OF CELLULAR BIOCHEMISTRY 149 - 149 1993.1

SEARCH FOR THE FUNCTIONAL SUBSTRATE PROTEINS OF PROTEIN-KINASES AND THEIR SELECTIVE INHIBITORS

H HIDAKA, M WATANABE, H TOKUMITSU

BIOLOGY AND MEDICINE OF SIGNAL TRANSDUCTION 24 485 - 490 1990

SEARCH FOR THE FUNCTIONAL SUBSTRATE PROTEINS OF PROTEIN-KINASES AND THEIR SELECTIVE INHIBITORS

H HIDAKA, M WATANABE, H TOKUMITSU

ADVANCES IN SECOND MESSENGER AND PHOSPHOPROTEIN RESEARCH 24 485 - 490 1990

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