Papers - TAKEYA Ryu
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Altered Fhod3 expression involved in progressive high-frequency hearing loss via dysregulation of actin polymerization stoichiometry in the cuticular plate. Reviewed International coauthorship
Boussaty EC, Ninoyu Y, Andrade LR, Li Q, Takeya R, Sumimoto H, Ohyama T, Wahlin KJ, Manor U, Friedman RA
PLoS genetics 20 ( 3 ) e1011211 2024.3
Language：English Publishing type：Research paper (scientific journal) Publisher：PLoS Genetics
Age-related hearing loss (ARHL) is a common sensory impairment with complex underlying mechanisms. In our previous study, we performed a meta-analysis of genome-wide association studies (GWAS) in mice and identified a novel locus on chromosome 18 associated with ARHL specifically linked to a 32 kHz tone burst stimulus. Consequently, we investigated the role of Formin Homology 2 Domain Containing 3 (Fhod3), a newly discovered candidate gene for ARHL based on the GWAS results. We observed Fhod3 expression in auditory hair cells (HCs) primarily localized at the cuticular plate (CP). To understand the functional implications of Fhod3 in the cochlea, we generated Fhod3 overexpression mice (Pax2-Cre+/-; Fhod3Tg/+) (TG) and HC-specific conditional knockout mice (Atoh1-Cre+/-; Fhod3fl/fl) (KO). Audiological assessments in TG mice demonstrated progressive high-frequency hearing loss, characterized by predominant loss of outer hair cells, and a decreased phalloidin intensities of CP. Ultrastructural analysis revealed loss of the shortest row of stereocilia in the basal turn of the cochlea, and alterations in the cuticular plate surrounding stereocilia rootlets. Importantly, the hearing and HC phenotype in TG mice phenocopied that of the KO mice. These findings suggest that balanced expression of Fhod3 is critical for proper CP and stereocilia structure and function. Further investigation of Fhod3 related hearing impairment mechanisms may lend new insight towards the myriad mechanisms underlying ARHL, which in turn could facilitate the development of therapeutic strategies for ARHL.
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Hikmawan Wahyu Sulistomo, Takayuki Nemoto, Yohko Kage, Hajime Fujii, Taku Uchida, Kogo Takamiya, Hideki Sumimoto, Hiroaki Kataoka, Haruhiko Bito, and Ryu Takeya
Cerebral Cortex 31 ( 4 ) 2205 - 2219 2020.11
Authorship：Last author, Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Cerebral Cortex
Changes in the shape and size of the dendritic spines are critical for synaptic transmission. These morphological changes depend on dynamic assembly of the actin cytoskeleton and occur differently in various types of neurons. However, how the actin dynamics are regulated in a neuronal cell type-specific manner remains largely unknown. We show that Fhod3, a member of the formin family proteins that mediate F-actin assembly, controls the dendritic spine morphogenesis of specific subpopulations of cerebrocortical pyramidal neurons. Fhod3 is expressed specifically in excitatory pyramidal neurons within layers II/III and V of restricted areas of the mouse cerebral cortex. Immunohistochemical and biochemical analyses revealed the accumulation of Fhod3 in postsynaptic spines. Although targeted deletion of Fhod3 in the brain did not lead to any defects in the gross or histological appearance of the brain, the dendritic spines in pyramidal neurons within presumptive Fhod3-positive areas were morphologically abnormal. In primary cultures prepared from the Fhod3-depleted cortex, defects in spine morphology were only detected in Fhod3 promoter-active cells, a small population of pyramidal neurons, and not in Fhod3 promoter-negative pyramidal neurons. Thus, Fhod3 plays a crucial role in dendritic spine morphogenesis only in a specific population of pyramidal neurons in a cell type-specific manner.
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Formin homology 2 domain-containing 3 (Fhod3) controls neural plate morphogenesis in mouse cranial neurulation by regulating multidirectional apical constriction. Reviewed
Sulistomo HW, Nemoto T, Yanagita T, Takeya R
The Journal of biological chemistry 294 ( 8 ) 2924 - 2934 2018.12
Language：English Publishing type：Research paper (scientific journal)
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Interaction between cardiac myosin-binding protein C and formin Fhod3 Reviewed
Matsuyama S., Kage Y., Fujimoto N., Ushijima T., Tsuruda T., Kitamura K., Shiose A., Asada Y., Sumimoto H., Takeya R.
Proceedings of the National Academy of Sciences of the United States of America 115 ( 19 ) E4386 - E4395 2018.5
Language：English Publishing type：Research paper (scientific journal) Publisher：Proceedings of the National Academy of Sciences of the United States of America
© 2018 National Academy of Sciences. All rights reserved. Mutations in cardiac myosin-binding protein C (cMyBP-C) are a major cause of familial hypertrophic cardiomyopathy. Although cMyBP-C has been considered to regulate the cardiac function via cross-bridge arrangement at the C-zone of the myosin-containing A-band, the mechanism by which cMyBP-C functions remains unclear. We identified formin Fhod3, an actin organizer essential for the formation and maintenance of cardiac sarcomeres, as a cMyBP-C–binding protein. The cardiac-specific N-terminal Ig-like domain of cMyBP-C directly interacts with the cardiac-specific N-terminal region of Fhod3. The interaction seems to direct the localization of Fhod3 to the C-zone, since a noncardiac Fhod3 variant lacking the cMyBP-C–binding region failed to localize to the C-zone. Conversely, the cardiac variant of Fhod3 failed to localize to the C-zone in the cMyBP-C–null mice, which display a phenotype of hypertrophic cardiomyopathy. The cardiomyopathic phenotype of cMyBP-C–null mice was further exacerbated by Fhod3 overexpression with a defect of sarcomere integrity, whereas that was partially ameliorated by a reduction in the Fhod3 protein levels, suggesting that Fhod3 has a deleterious effect on cardiac function under cMyBP-C–null conditions where Fhod3 is aberrantly mislocalized. Together, these findings suggest the possibility that Fhod3 contributes to the pathogenesis of cMyBP-C–related cardiomyopathy and that Fhod3 is critically involved in cMyBP-C–mediated regulation of cardiac function via direct interaction.
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Ushijima T., Fujimoto N., Matsuyama S., Kan-O M., Kiyonari H., Shioi G., Kage Y., Yamasaki S., Takeya R., Sumimoto H.
Journal of Biological Chemistry 293 ( 1 ) 148 - 162 2018.1
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Biological Chemistry
© 2018 by The American Society for Biochemistry and Molecular Biology, Inc. Cardiac development and function require actin-myosin interactions in the sarcomere, a highly organized contractile structure. Sarcomere assembly mediated by formin homology 2 domain-containing 3 (Fhod3), a member of formins that directs formation of straight actin filaments, is essential for embryonic cardiogenesis. However, the role of Fhod3 in the neonatal and adult stages has remained unknown. Here, we generated floxed Fhod3 mice to bypass the embryonic lethality of an Fhod3 knockout (KO). Perinatal KO of Fhod3 in the heart caused juvenile lethality at around day 10 after birth with enlarged hearts composed of severely impaired myofibrils, indicating that Fhod3 is crucial for postnatal heart development. Tamoxifeninduced conditional KO of Fhod3 in the adult heart neither led to lethal effects nor did it affect sarcomere structure and localization of sarcomere components. However, adult Fhod3-deleted mice exhibited a slight cardiomegaly and mild impairment of cardiac function, conditions that were sustained over 1 year without compensation during aging. In addition to these agerelated changes, systemic stimulation with the α1-adrenergic receptor agonist phenylephrine, which induces sustained hypertension and hypertrophy development, induced expression of fetal cardiac genes that was more pronounced in adult Fhod3- deleted mice than in the control mice, suggesting that Fhod3 modulates hypertrophic changes in the adult heart. We conclude that Fhod3 plays a crucial role in both postnatal cardiac development and functional maintenance of the adult heart.
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The expression of the formin Fhod3 in mouse tongue striated muscle Reviewed International coauthorship
Nakagawa Hikaru, Kage Yohko, Miura Ayako, Wahyu Sulistomo Hikmawan, Matsuyama Sho, Yamashita Yoshihiro, Takeya Ryu
Cell Structure and Function 49 ( 2 ) 111 - 122 2024.11
Authorship：Last author, Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Japan Society for Cell Biology
The sarcomere is the contractile unit of striated muscle and is composed of actin and myosin filaments. There is increasing evidence to support that actin assembly mediated by Fhod3, a member of the formin family of proteins, is critical for sarcomere formation and maintenance in cardiac muscle. Fhod3, which is abundantly expressed in the heart, localizes to the center of sarcomeres and contributes to the regulation of the cardiac function, as evidenced by the fact that mutations in Fhod3 cause cardiomyopathy. However, the role of Fhod3 in skeletal muscle, another type of striated muscle, is unclear. We herein show that Fhod3 is expressed in the tongue at both mRNA and protein levels, although in smaller amounts than in the heart. To determine the physiological role of Fhod3 expressed in the tongue, we generated embryos lacking Fhod3 in the tongue. The tongue tissue of the Fhod3-depleted embryos did not show any significant structural defects, suggesting that Fhod3 is dispensable for normal development of the mouse tongue. Unexpectedly, the immunostaining analysis revealed the absence of specific sarcomeric signals for Fhod3 in the wild-type tongue when compared to the Fhod3-depleted tongue as a negative control, despite the use of antibodies that had previously been validated by immunostaining of heart tissues. Taken together, although Fhod3 protein is expressed at a significant level in the tongue, Fhod3 in the tongue does not appear to exhibit the same sarcomeric pattern as observed in the heart, suggesting a different role for Fhod3 in the tongue muscles.Key words: actin, formin, sarcomere, striated muscle
DOI： 10.1247/csf.24044
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Maruta, Toyoaki; Kouroki, Satoshi; Kurogi, Mio; Hidaka, Kotaro; Koshida, Tomohiro; Miura, Ayako; Nakagawa, Hikaru; Yanagita, Toshihiko; Takeya, Ryu; Tsuneyoshi, Isao.
Journal of Neuroscience Research 102 ( 10 ) e25386 2024
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Neuroscience Research
Voltage-gated sodium channels, including NaV1.7, NaV1.8, and NaV1.9, play important roles in pain transmission and chronic pain development. However, the specific mechanisms of their action remain unclear, highlighting the need for in vivo stimulation studies of these channels. Optogenetics, a novel technique for targeting the activation or inhibition of specific neural circuits using light, offers a promising solution. In our previous study, we used optogenetics to selectively excite NaV1.7-expressing neurons in the dorsal root ganglion of mice to induce nocifensive behavior. Here, we further characterize the impact of nocifensive behavior by activation of NaV1.7, NaV1.8, or NaV1.9-expressing neurons. Using CRISPR/Cas9-mediated homologous recombination, NaV1.7–iCre, NaV1.8–iCre, or NaV1.9–iCre mice expressing iCre recombinase under the control of the endogenous NaV1.7, NaV1.8, or NaV1.9 gene promoter were produced. These mice were then bred with channelrhodopsin-2 (ChR2) Cre–reporter Ai32 mice to obtain NaV1.7–ChR2, NaV1.8–ChR2, or NaV1.9–ChR2 mice. Blue light exposure triggered paw withdrawal in all mice, with the strongest response in NaV1.8–ChR2 mice. These light sensitivity differences observed across NaV1.x–ChR2 mice may be dependent on ChR2 expression or reflect the inherent disparities in their pain transmission roles. In conclusion, we have generated noninvasive pain models, with optically activated peripheral nociceptors. We believe that studies using optogenetics will further elucidate the role of sodium channel subtypes in pain transmission.
DOI： 10.1002/jnr.25386
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Effectiveness of Interprofessional Education Based on the Case-and Communication-Based Approach. Reviewed
武谷 立
IAFOR Journal of Psychology & the Behavioral Sciences 9 3 2024
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Koshida T., Maruta T., Tanaka N., Hidaka K., Kurogi M., Nemoto T., Yanagita T., Takeya R., Tsuneyoshi I.
Acta Medica Okayama 77 ( 4 ) 359 - 364 2023
Language：English Publishing type：Research paper (scientific journal) Publisher：Acta Medica Okayama
Pulsed radiofrequency (PRF) is a safe method of treating neuropathic pain by generating intermittent electric fields at the needle tip. Resiniferatoxin (RTX) is an ultrapotent agonist of transient receptor potential vanilloid subtype-1 (TRPV1) receptors. We investigated the mechanism of PRF using a rat model of RTX-induced neuropathic pain. After administering RTX intraperitoneally, PRF was applied to the right sciatic nerve. We observed the changes in TRPV1, calcitonin gene-related peptide (CGRP), and brain-derived neurotrophic factor (BDNF) in the dorsal root ganglia by western blotting. Expressions of TRPV1 and CGRP were significantly lower in the contralateral (RTX-treated, PRF-untreated) tissue than in control rats (p<0.0001 and p<0.0001, respectively) and the ipsilateral tissues (p<0.0001 and p<0.0001, respectively). BDNF levels were significantly higher in the contralateral tissues than in the control rats (p<0.0001) and the ipsilateral tissues (p<0.0001). These results suggest that, while TRPV1 and CGRP are decreased by RTX-induced neuronal damage, increased BDNF levels result in pain development. PRF may promote recovery from neuronal damage with concomitant restoration of TRPV1 and CGRP, and exert its analgesic effect by reversing BDNF increase. Further research is required to understand the role of TRPV1 and CGRP restoration in improving mechanical allodynia.
DOI： 10.18926/AMO/65741
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Selective optogenetic activation of NaV1.7-expressing afferents in NaV1.7-ChR2 mice induces nocifensive behavior without affecting responses to mechanical and thermal stimuli. Reviewed
Maruta T, Hidaka K, Kouroki S, Koshida T, Kurogi M, Kage Y, Mizuno S, Shirasaka T, Yanagita T, Takahashi S, Takeya R, Tsuneyoshi I
PloS one 17 ( 10 ) e0275751 2022.10
Language：English Publishing type：Research paper (scientific journal)
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Extracellular signal-regulated kinase phosphorylation enhancement and NaV1.7 sodium channel upregulation in rat dorsal root ganglia neurons contribute to resiniferatoxin-induced neuropathic pain: The efficacy and mechanism of pulsed radiofrequency therapy. Reviewed
Hidaka K, Maruta T, Koshida T, Kurogi M, Kage Y, Kouroki S, Shirasaka T, Takeya R, Tsuneyoshi I
Molecular pain 18 17448069221089784 2022.4
Language：English Publishing type：Research paper (scientific journal)
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Nursing pharmacology education and active-learning. Reviewed
Yanagita Toshihiko, Kanaoka Maki, Kinoshita Yumiko, Takeya Ryu
Folia Pharmacologica Japonica 157 ( 2 ) 104 - 109 2022.3
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：The Japanese Pharmacological Society
<p>Comprehensive pharmacology education in nursing based on the "Patient-oriented Pharmacology" is effective against the improvement of quality of pharmacotherapy and patient satisfaction. Two active learning programs of practical pharmacotherapy for nursing students have been performed in School of Nursing, University of Miyazaki; (1) pharmacotherapy role-play for interprofessional education (IPE) and (2) practical excise for Kampo medicine. Pharmacotherapy role-play for IPE was performed as joint lecture both medical students and nursing students. This pharmacotherapy role-play is named Case & Communication based approach (C&C approach), since it is studied through communication between physicians, nurses and patients based on cases presented beforehand. In the practical excise for Kampo medicine, nursing students studied Kampo medicines and tried to taste 9 frequently used Kampo medicines. These active-learning programs in nursing pharmacology education may be effective for better understanding of pharmacotherapy and patient's feeling, and improvement of students' motivation as a nurse.</p>
DOI： 10.1254/fpj.21100
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Differential effects of the formin inhibitor SMIFH2 on contractility and Ca2+ handling in frog and mouse cardiomyocytes Reviewed International journal
Koji Sakata, Sho Matsuyama, Nagomi Kurebayashi, Kengo Hayamizu, Takashi Murayama, Kunihide Nakamura, Kazuo Kitamura, Sachio Morimoto, Ryu Takeya
Genes to Cells 26 ( 8 ) 583 - 595 2021.8
Authorship：Last author, Corresponding author Language：Japanese Publishing type：Research paper (scientific journal)
Genetic mutations in actin regulators have been emerging as a cause of cardiomyopathy, although the functional link between actin dynamics and cardiac contraction remains largely unknown. To obtain insight into this issue, we examined the effects of pharmacological inhibition of formins, a major class of actin-assembling proteins. The formin inhibitor SMIFH2 significantly enhanced the cardiac contractility of isolated frog hearts, thereby augmenting cardiac performance. SMIFH2 treatment had no significant effects on the Ca2+ sensitivity of frog muscle fibers. Instead, it unexpectedly increased Ca2+ concentrations of isolated frog cardiomyocytes, suggesting that the inotropic effect is due to enhanced Ca2+ transients. In contrast to frog hearts, the contractility of mouse cardiomyocytes was attenuated by SMIFH2 treatment with decreasing Ca2+ transients. Thus, SMIFH2 has opposing effects on the Ca2+ transient and contractility between frog and mouse cardiomyocytes. We further found that SMIFH2 suppressed Ca2+ -release via type 2 ryanodine receptor (RyR2); this inhibitory effect may explain the species differences, since RyR2 is critical for Ca2+ transients in mouse myocardium but absent in frog myocardium. Although the mechanisms underlying the enhancement of Ca2+ transients in frog cardiomyocytes remain unclear, SMIFH2 differentially affects the cardiac contraction of amphibian and mammalian by differentially modulating their Ca2+ handling.
DOI： 10.1111/gtc.12873
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Toyoaki Maruta, Takayuki Nemoto, Koutaro Hidaka, Tomohiro Koshida, Tetsuro Shirasaka, Toshihiko Yanagita, Ryu Takeya Isao Tsuneyoshi
PLoS ONE 14 ( 11 ) e0225586 2019.11
Language：English Publishing type：Research paper (scientific journal) Publisher：PLoS ONE
© 2019 Maruta et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Oxaliplatin is the first-line chemotherapy for metastatic colorectal cancer. Unlike other platinum anticancer agents, oxaliplatin does not result in significant renal impairment and ototoxicity. Oxaliplatin, however, has been associated with acute and chronic peripheral neuropathies. Despite the awareness of these side-effects, the underlying mechanisms are yet to be clearly established. Therefore, in this study, we aimed to understand the factors involved in the generation of chronic neuropathy elicited by oxaliplatin treatment. We established a rat model of oxaliplatin-induced neuropathic pain (4 mg kg-1 intraperitoneally). The paw withdrawal thresholds were assessed at different time-points after the treatment, and a significant decrease was observed 3 and 4 weeks after oxaliplatin treatment as compared to the vehicle treatment (4.4 ± 1.0 vs. 16.0 ± 4.1 g; P < 0.05 and 4.4 ± 0.7 vs. 14.8 ± 3.1 g; P < 0.05, respectively). We further evaluated the role of different mitogen-activated protein kinases (MAPKs) pathways in the pathophysiology of neuropathic pain. Although the levels of total extracellular signal-regulated kinase (ERK) 1/2 in the dorsal root ganglia (DRG) were not different between oxaliplatin and vehicle treatment groups, phosphorylated ERK (pERK) 1/2 was up-regulated up to 4.5-fold in the oxaliplatin group. Administration of ERK inhibitor PD98059 (6 μg day-1 intrathecally) inhibited oxaliplatin-induced ERK phosphorylation and neuropathic pain. Therefore, upregulation of p-ERK by oxaliplatin in rat DRG and inhibition of mechanical allodynia by an ERK inhibitor in the present study may provide a better understanding of intracellular molecular alterations associated with oxaliplatin-induced neuropathic pain and help in the development of potential therapeutics.
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Sanematsu F., Kanai A., Ushijima T., Shiraishi A., Abe T., Kage Y., Sumimoto H., Takeya R.
Cytoskeleton 76 ( 2 ) 219 - 229 2019.4
Language：English Publishing type：Research paper (scientific journal) Publisher：Cytoskeleton
The formin family proteins have the ability to regulate actin filament assembly, thereby functioning in diverse cytoskeletal processes. Fhod3, a cardiac member of the family, plays a crucial role in development and functional maintenance of the heart. Although Fhod1, a protein closely-related to Fhod3, has been reported to be expressed in cardiomyocytes, the role of Fhod1 in the heart has still remained elusive. To know the physiological role of Fhod1 in the heart, we disrupted the Fhod1 gene in mice by replacement of exon 1 with a lacZ reporter gene. Histological lacZ staining unexpectedly revealed no detectable expression of Fhod1 in the heart, in contrast to intensive staining in the lung, a Fhod1-containing organ. Consistent with this, expression level of the Fhod1 protein in the heart was below the lower limit of detection of the present immunoblot analysis with three independent anti-Fhod1 antibodies. Homozygous Fhod1-null mice did not show any defects in gross and histological appearance of the heart or upregulate fetal cardiac genes that are induced under stress conditions. Furthermore, Fhod1 ablation did not elicit compensatory increase in expression of other formins. Thus, Fhod1 appears to be dispensable for normal development and function of the mouse heart, even if a marginal amount of Fhod1 is expressed in the heart.
DOI： 10.1002/cm.21523
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Fujimoto N., Kan-O M., Ushijima T., Kage Y., Tominaga R., Sumimoto H., Takeya R.
PLoS ONE 11 ( 2 ) e0148472 2016.2
Language：English Publishing type：Research paper (scientific journal) Publisher：PLoS ONE
© 2016 Fujimoto et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Fhod3 is a cardiac member of the formin family proteins that play pivotal roles in actin filament assembly in various cellular contexts. The targeted deletion of mouse Fhod3 gene leads to defects in cardiogenesis, particularly during myofibrillogenesis, followed by lethality at embryonic day (E) 11.5. However, it remains largely unknown how Fhod3 functions during myofibrillogenesis. In this study, to assess the mechanism whereby Fhod3 regulates myofibrillogenesis during embryonic cardiogenesis, we generated transgenic mice expressing Fhod3 selectively in embryonic cardiomyocytes under the control of the β-myosin heavy chain (MHC) promoter. Mice expressing wild-Type Fhod3 in embryonic cardiomyocytes survive to adulthood and are fertile, whereas those expressing Fhod3 (I1127A) defective in binding to actin die by E11.5 with cardiac defects. This cardiac phenotype of the Fhod3 mutant embryos is almost identical to that observed in Fhod3 null embryos, suggesting that the actin-binding activity of Fhod3 is crucial for embryonic cardiogenesis. On the other hand, the β-MHC promoter-driven expression of wild-Type Fhod3 sufficiently rescues cardiac defects of Fhod3-null embryos, indicating that the Fhod3 protein expressed in a transgenic manner can function properly to achieve myofibril maturation in embryonic cardiomyocytes. Using the transgenic mice, we further examined detailed localization of Fhod3 during myofibrillogenesis in situ and found that Fhod3 localizes to the specific central region of nascent sarcomeres prior to massive rearrangement of actin filaments and remains there throughout myofibrillogenesis. Taken together, the present findings suggest that, during embryonic cardiogenesis, Fhod3 functions as the essential reorganizer of actin filaments at the central region of maturating sarcomeres via the actin-binding activity of the FH2 domain.
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心筋の収縮装置「サルコメア」の形成の分子機構
武谷 立
生存科学 J.Seizon and Life Sci 26 ( 1 ) 299 - 305 2015.9
Language：English Publishing type：Research paper (scientific journal)
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Yanagita Toshihiko, Nemoto Takayuki, Takeya Ryu
Folia Pharmacologica Japonica 146 ( 2 ) 115 - 8 2015.8
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：The Japanese Pharmacological Society
DOI： 10.1254/fpj.146.115
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Novel human homologues of p47phox and p67phox participate in activation of superoxide-producing NADPH oxidases.
Takeya R, Ueno N, Kami K, Taura M, Kohjima M, Izaki T, Nunoi H, Sumimoto H
The Journal of biological chemistry 290 ( 10 ) 6003 2015.3
Language：Japanese Publishing type：Research paper (scientific journal)
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Arimura T., Takeya R., Ishikawa T., Yamano T., Matsuo A., Tatsumi T., Nomura T., Sumimoto H., Kimura A.
Circulation Journal 77 ( 12 ) 2990 - 2996 2013.11
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Circulation Journal
Background: Dilated cardiomyopathy (DCM) is characterized by a dilated left ventricular cavity with systolic dysfunction manifested by heart failure. It has been revealed that mutations in genes for cytoskeleton or sarcomere proteins cause DCM. However, the disease-causing mutations can be found only in far less than half of patients with a family history, indicating that there should be other disease genes for DCM. Formin homology 2 domain containing 3 (FHOD3) is a sarcomeric protein expressed in the heart that plays an essential role in sarcomere organization during myofibrillogenesis. The purpose of this study was to explore a possible novel disease gene for DCM. Methods and Results: We analyzed 48 Japanese familial DCM patients for mutations in FHOD3, and a missense variant, Tyr1249Asn, which was predicted to modify the 3D structure and damage protein function, was found in a case with adult-onset DCM. Functional studies revealed that the DCM-associated mutation significantly reduced the ability to induce actin dynamics-dependent activation of serum response factor, although no remarkable change in the cellular localization was induced in neonatal rat cardiomyocytes transfected with a mutant construct of FHOD3. Conclusions: The DCM-associated FHOD3 variant may cause DCM by interfering with actin filament assembly.
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Phosphorylation of Noxo1 at threonine 341 regulates its interaction with Noxa1 and the superoxide-producing activity of Nox1.
Yamamoto A, Takeya R, Matsumoto M, Nakayama KI, Sumimoto H
The FEBS journal 280 ( 20 ) 5145 - 59 2013.10
Language：Japanese Publishing type：Research paper (scientific journal)
DOI： 10.1111/febs.12489
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Dilated cardiomyopathy-associated FHOD3 variant impairs the ability to induce activation of transcription factor serum response factor.
Arimura T, Takeya R, Ishikawa T, Yamano T, Matsuo A, Tatsumi T, Nomura T, Sumimoto H, Kimura A
Circulation journal : official journal of the Japanese Circulation Society 77 ( 12 ) 2990 - 6 2013
Language：Japanese Publishing type：Research paper (scientific journal)
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Mammalian formin Fhod3 plays an essential role in cardiogenesis by organizing myofibrillogenesis.
Kan-O M, Takeya R, Abe T, Kitajima N, Nishida M, Tominaga R, Kurose H, Sumimoto H
Biology open 1 ( 9 ) 889 - 96 2012.9
Language：Japanese Publishing type：Research paper (scientific journal)
DOI： 10.1242/bio.20121370
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High cell-autonomy of the anterior endomesoderm viewed in blastomere fate shift during regulative development in the isolated right halves of four-cell stage Xenopus embryos.
Koga M, Nakashima T, Matsuo S, Takeya R, Sumimoto H, Sakai M, Kageura H
Development, growth & differentiation 54 ( 7 ) 717 - 29 2012.9
Language：Japanese Publishing type：Research paper (scientific journal)
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Expression and subcellular localization of mammalian formin Fhod3 in the embryonic and adult heart.
Kan-o M, Takeya R, Taniguchi K, Tanoue Y, Tominaga R, Sumimoto H
PloS one 7 ( 4 ) e34765 2012
Language：Japanese Publishing type：Research paper (scientific journal)
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A conserved region between the TPR and activation domains of p67phox participates in activation of the phagocyte NADPH oxidase.
Maehara Y, Miyano K, Yuzawa S, Akimoto R, Takeya R, Sumimoto H
The Journal of biological chemistry 285 ( 41 ) 31435 - 45 2010.10
Language：Japanese Publishing type：Research paper (scientific journal)
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Mammalian formin fhod3 regulates actin assembly and sarcomere organization in striated muscles.
Taniguchi K, Takeya R, Suetsugu S, Kan-O M, Narusawa M, Shiose A, Tominaga R, Sumimoto H
The Journal of biological chemistry 284 ( 43 ) 29873 - 81 2009.10
Language：Japanese Publishing type：Research paper (scientific journal)
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A region N-terminal to the tandem SH3 domain of p47phox plays a crucial role in the activation of the phagocyte NADPH oxidase.
Taura M, Miyano K, Minakami R, Kamakura S, Takeya R, Sumimoto H
The Biochemical journal 419 ( 2 ) 329 - 38 2009.4
Language：Japanese Publishing type：Research paper (scientific journal)
DOI： 10.1042/BJ20082028
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Enhanced expression of NADPH oxidase Nox4 in human gliomas and its roles in cell proliferation and survival.
Shono T, Yokoyama N, Uesaka T, Kuroda J, Takeya R, Yamasaki T, Amano T, Mizoguchi M, Suzuki SO, Niiro H, Miyamoto K, Akashi K, Iwaki T, Sumimoto H, Sasaki T
International journal of cancer 123 ( 4 ) 787 - 92 2008.8
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The mammalian formin FHOD1 is activated through phosphorylation by ROCK and mediates thrombin-induced stress fibre formation in endothelial cells.
Takeya R, Taniguchi K, Narumiya S, Sumimoto H
The EMBO journal 27 ( 4 ) 618 - 28 2008.2
Language：Japanese Publishing type：Research paper (scientific journal)
DOI： 10.1038/emboj.2008.7
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Full-length p40phox structure suggests a basis for regulation mechanism of its membrane binding.
Honbou K, Minakami R, Yuzawa S, Takeya R, Suzuki NN, Kamakura S, Sumimoto H, Inagaki F
The EMBO journal 26 ( 4 ) 1176 - 86 2007.2
Language：Japanese Publishing type：Research paper (scientific journal)
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Interaction between the SH3 domains and C-terminal proline-rich region in NADPH oxidase organizer 1 (Noxo1).
Yamamoto A, Kami K, Takeya R, Sumimoto H
Biochemical and biophysical research communications 352 ( 2 ) 560 - 5 2007.1
Language：Japanese Publishing type：Research paper (scientific journal)
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Expression of isoforms of NADPH oxidase components in rat pancreatic islets.
Uchizono Y, Takeya R, Iwase M, Sasaki N, Oku M, Imoto H, Iida M, Sumimoto H
Life sciences 80 ( 2 ) 133 - 9 2006.12
Language：Japanese Publishing type：Research paper (scientific journal)
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Regulation of novel superoxide-producing NAD(P)H oxidases.
Takeya R, Sumimoto H
Antioxidants & redox signaling 8 ( 9-10 ) 1523 - 32 2006.9
Language：Japanese Publishing type：Research paper (scientific journal)
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Direct involvement of the small GTPase Rac in activation of the superoxide-producing NADPH oxidase Nox1.
Miyano K, Ueno N, Takeya R, Sumimoto H
The Journal of biological chemistry 281 ( 31 ) 21857 - 68 2006.8
Language：Japanese Publishing type：Research paper (scientific journal)
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Expression and function of Noxo1gamma, an alternative splicing form of the NADPH oxidase organizer 1.
Takeya R, Taura M, Yamasaki T, Naito S, Sumimoto H
The FEBS journal 273 ( 16 ) 3663 - 77 2006.8
Language：Japanese Publishing type：Research paper (scientific journal)
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Activation of the superoxide-producing phagocyte NADPH oxidase requires co-operation between the tandem SH3 domains of p47phox in recognition of a polyproline type II helix and an adjacent alpha-helix of p22phox.
Nobuhisa I, Takeya R, Ogura K, Ueno N, Kohda D, Inagaki F, Sumimoto H
The Biochemical journal 396 ( 1 ) 183 - 92 2006.5
Language：Japanese Publishing type：Research paper (scientific journal)
DOI： 10.1042/BJ20051899
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NMR solution structure of the tandem Src homology 3 domains of p47phox complexed with a p22phox-derived proline-rich peptide.
Ogura K, Nobuhisa I, Yuzawa S, Takeya R, Torikai S, Saikawa K, Sumimoto H, Inagaki F
The Journal of biological chemistry 281 ( 6 ) 3660 - 8 2006.2
Language：Japanese Publishing type：Research paper (scientific journal)
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[Phagocytosis and killing of microorganisms].
Minakami R, Takeya R, Sumimoto H
Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme 51 ( 2 ) 109 - 17 2006.2
Language：Japanese Publishing type：Research paper (scientific journal)
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Phagocytosis and killing of microorganisms
Minakami R., Takeya R., Sumimoto H.
Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme 51 ( 2 ) 109 - 117 2006.2
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme
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Regulation of superoxide-producing NADPH oxidases in nonphagocytic cells.
Takeya R, Ueno N, Sumimoto H
Methods in enzymology 406 456 - 68 2006
Language：Japanese Publishing type：Research paper (scientific journal)
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Mizuki K., Takeya R., Kuribayashi F., Nobuhisa I., Kohda D., Nunoi H., Takeshige K., Sumimoto H.
Archives of Biochemistry and Biophysics 444 ( 2 ) 185 - 194 2005.12
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Archives of Biochemistry and Biophysics
Activation of the phagocyte NADPH oxidase requires the regulatory proteins p47 phox and p67 phox , each harboring two SH3 domains. p67 phox interacts with p47 phox via simultaneous binding of the p67 phox C-terminal SH3 domain to both the proline-rich region (PRR) of amino acid residues 360-369 and its C-terminally flanking region of p47 phox ; the role of the interaction in oxidase regulation has not been fully understood. Here we show that the p47 phox -p67 phox interaction is disrupted not only by deletion of the PRR but also by substitution for basic residues in the extra-PRR (K383E/K385E). The substitution impaired oxidase activation partially in vitro and much more profoundly in vivo, indicating the significance of the p47 phox extra-PRR. Replacement of Ser-379 in the extra-PRR, a residue known to undergo phosphorylation in stimulated cells, by aspartate attenuates the interaction and thus results in a defective superoxide production, suggesting that phosphorylation of Ser-379 is involved in oxidase regulation. © 2005 Elsevier Inc. All rights reserved.
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Molecular composition and regulation of the Nox family NAD(P)H oxidases.
Sumimoto H, Miyano K, Takeya R
Biochemical and biophysical research communications 338 ( 1 ) 677 - 86 2005.12
Language：Japanese Publishing type：Research paper (scientific journal)
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PDIP38 associates with proteins constituting the mitochondrial DNA nucleoid.
Cheng X, Kanki T, Fukuoh A, Ohgaki K, Takeya R, Aoki Y, Hamasaki N, Kang D
Journal of biochemistry 138 ( 6 ) 673 - 8 2005.12
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The superoxide-producing NAD(P)H oxidase Nox4 in the nucleus of human vascular endothelial cells.
Kuroda J, Nakagawa K, Yamasaki T, Nakamura K, Takeya R, Kuribayashi F, Imajoh-Ohmi S, Igarashi K, Shibata Y, Sueishi K, Sumimoto H
Genes to cells : devoted to molecular & cellular mechanisms 10 ( 12 ) 1139 - 51 2005.12
Language：Japanese Publishing type：Research paper (scientific journal)
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Isoform-specific membrane targeting mechanism of Rac during Fc gamma R-mediated phagocytosis: positive charge-dependent and independent targeting mechanism of Rac to the phagosome.
Ueyama T, Eto M, Kami K, Tatsuno T, Kobayashi T, Shirai Y, Lennartz MR, Takeya R, Sumimoto H, Saito N
Journal of immunology (Baltimore, Md. : 1950) 175 ( 4 ) 2381 - 90 2005.8
Language：Japanese Publishing type：Research paper (scientific journal)
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Ueyama T., Eto M., Kami K., Tatsuno T., Kobayashi T., Shirai Y., Lennartz M., Takeya R., Sumimoto H., Saito N.
Journal of Immunology 175 ( 4 ) 2381 - 2390 2005.8
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Journal of Immunology
Rac1 and Rac2 are capable of stimulating superoxide production in vitro, but their targeting and functional mechanisms are still unknown. In the present study, we found that Rac1, 2, and 3 all accumulate at the phagosome during FcγR-mediated phagocytosis, and that the order of accumulation (Rac1 > Rac3 > Rac2) depends on the net positive charge in their polybasic (PB) regions (183-188 aa). Although all GFP-tagged prenylated PB regions of Rac isoforms (GFP-Rac(PB)) and GFP-tagged prenylated 6 Ala (GFP-6A) accumulated during phagocytosis, GFP-Rac2(PB) and GFP-6A showed weak accumulation at the phagosome through a linear structure connecting the phagosome and endomembranes. The PB region of Rac1 showed strong phospholipid interaction with PI(3)P, PI(4)P, PI(5)P, PI(3,4,5)P 3 , and phosphatidic acid, however, that of Rac1 did not. Constitutively active Rac2, GFP-Rac2(Q61L), was predominantly localized at the endomembranes; these endomembranes fused to the phagosome through the linear structure during phagocytosis, and this accumulation mechanism did not depend on positive charge in the PB region. Our conclusion is that Rac1 directly targets to the phagosome using the positively charged PB region and this accumulation mechanism is likely enhanced by the phospholipids. In addition to this mechanism, Rac2 has a positive charge-independent mechanism in which Rac2 initially targets to endomembranes and then these endomembranes fuse to the phagosome. Copyright © 2005 by The American Association of Immunologists, Inc.
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Fhos2, a novel formin-related actin-organizing protein, probably associates with the nestin intermediate filament.
Kanaya H, Takeya R, Takeuchi K, Watanabe N, Jing N, Sumimoto H
Genes to cells : devoted to molecular & cellular mechanisms 10 ( 7 ) 665 - 78 2005.7
Language：Japanese Publishing type：Research paper (scientific journal)
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The NADPH oxidase Nox3 constitutively produces superoxide in a p22phox-dependent manner: its regulation by oxidase organizers and activators.
Ueno N, Takeya R, Miyano K, Kikuchi H, Sumimoto H
The Journal of biological chemistry 280 ( 24 ) 23328 - 39 2005.6
Language：Japanese Publishing type：Research paper (scientific journal)
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Structure of a cell polarity regulator, a complex between atypical PKC and Par6 PB1 domains.
Hirano Y, Yoshinaga S, Takeya R, Suzuki NN, Horiuchi M, Kohjima M, Sumimoto H, Inagaki F
The Journal of biological chemistry 280 ( 10 ) 9653 - 61 2005.3
Language：Japanese Publishing type：Research paper (scientific journal)
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Helicobacter pylori lipopolysaccharide activates Rac1 and transcription of NADPH oxidase Nox1 and its organizer NOXO1 in guinea pig gastric mucosal cells.
Kawahara T, Kohjima M, Kuwano Y, Mino H, Teshima-Kondo S, Takeya R, Tsunawaki S, Wada A, Sumimoto H, Rokutan K
American journal of physiology. Cell physiology 288 ( 2 ) C450 - 7 2005.2
Language：Japanese Publishing type：Research paper (scientific journal)
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On the mechanism of cell lysis by deformation.
Takamatsu H, Takeya R, Naito S, Sumimoto H
Journal of biomechanics 38 ( 1 ) 117 - 24 2005.1
Language：Japanese Publishing type：Research paper (scientific journal)
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Molecular mechanism underlying activation of superoxide-producing NADPH oxidases: roles for their regulatory proteins.
Sumimoto H, Ueno N, Yamasaki T, Taura M, Takeya R
Japanese journal of infectious diseases 57 ( 5 ) S24 - 5 2004.10
Language：Japanese Publishing type：Research paper (scientific journal)
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Sumimoto H., Ueno N., Yamasaki T., Taura M., Takeya R.
Japanese Journal of Infectious Diseases 57 ( 5 ) 2004.10
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Japanese Journal of Infectious Diseases
The phagocyte NADPH oxidase is dormant in resting cells but becomes activated during phagocytosis to produce superoxide, a precursor of microbicidal oxidants, thereby playing a crucial role in host defence. The catalytic core of this enzyme comprises the two membranous subunits gp91 phox /Nox2 and p22 phox . The oxidase activation requires the small GTPase Rae and the SH3 domain-containing proteins p47 phox and p67 phox , they normally exist in the cytoplasm and translocate upon cell stimulation to the membrane. The translocation depends on a stimulus-induced conformational change of p47 phox , which leads to the SH3 domain-mediated interaction with p22 phox , a binding required for the gp96 phox /Nox2-dependent super-oxide production. Activation of Nox1, an oxidase that is likely involved in host defence at the colon, requires novel proteins homologous to p47 phox and p67 phox , designated Noxo1 and Noxa1, respectively. Noxo1 and Noxa1, both expressed abundantly in the colon, are capable of constitutively activating Nox1. The constitutive activation may be due to the property of Noxo1: in contrast with p47 phox , Noxo1 seems to normally associate with p22 phox , which is required for the Nox1 activation. We will also describe the mechanism underlying regulation of the third oxidase Nox3, which exits in fetal kidney and inner ears.
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Identification of a novel type 1 diabetes susceptibility gene, T-bet.
Sasaki Y, Ihara K, Matsuura N, Kohno H, Nagafuchi S, Kuromaru R, Kusuhara K, Takeya R, Hoey T, Sumimoto H, Hara T
Human genetics 115 ( 3 ) 177 - 84 2004.8
Language：Japanese Publishing type：Research paper (scientific journal)
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Identification of a novel type 1 diabetes susceptibility gene, T-bet
Sasaki Y., Ihara K., Matsuura N., Kohno H., Nagafuchi S., Kuromaru R., Kusuhara K., Takeya R., Hoey T., Sumimoto H., Hara T.
Human Genetics 115 ( 3 ) 177 - 184 2004.8
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Human Genetics
The gene encoding interferon (IFN)-γ, IFNG, is known as one of the candidate susceptibility genes for type 1 diabetes. In addition, cytokines, including IFN-γ, play important roles in the pathogenesis of type 1 diabetes. Therefore, we focused on the Th1-specific T-box transcription factor gene (T-bet), which contributes to the induction of the hallmark Th1 cytokine, IFN-γ. We first screened for polymorphisms in the T-bet gene and detected two microsatellite repeat polymorphisms located in intron 1 and the 3′- flanking region, and two single nucleotide polymorphisms, including a His33Gln substitution within the coding region. By association studies, the Gln-positive phenotype and (CA) 14 allele in 3′-flanking region of T-bet were found to be associated with type 1 diabetes in the Japanese population. Furthermore, Gln33 T-bet showed a significantly higher transcriptional activity of the IFNG gene via a dual luciferase reporter assay. Our study suggests the first evidence of an association between type 1 diabetes and polymorphisms in the T-bet gene, and that variation in T-bet transcriptional activity may play a role in the development of type 1 diabetes, possibly through the effect on IFN-γ production in Th1 cells. © Springer-Verlag 2004.
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Role of nicotinamide adenine dinucleotide phosphate oxidase 1 in oxidative burst response to Toll-like receptor 5 signaling in large intestinal epithelial cells.
Kawahara T, Kuwano Y, Teshima-Kondo S, Takeya R, Sumimoto H, Kishi K, Tsunawaki S, Hirayama T, Rokutan K
Journal of immunology (Baltimore, Md. : 1950) 172 ( 5 ) 3051 - 8 2004.3
Language：Japanese Publishing type：Research paper (scientific journal)
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Kawahara T., Kuwano Y., Teshima-Kondo S., Takeya R., Sumimoto H., Kishi K., Tsunawaki S., Hirayama T., Rokutan K.
Journal of Immunology 172 ( 5 ) 3051 - 3058 2004.3
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Journal of Immunology
The NADPH oxidase 1 (Nox1) is a gp91 phox homologue preferentially expressed in the colon. We have established primary cultures of guinea pig large intestinal epithelial cells giving 90% purity of surface mucous cells. These cells spontaneously released superoxide anion (O 2 - ) of 160 nmol/mg protein/h and expressed the Nox1, p22 phox , p67 phox , and Rac1 mRNAs, but not the gp91 phox , Nox4, p47 phox , p40 phox , and Rac2 mRNAs. They also expressed novel homologues of p47 phox and p67 phox (p41 nox and p51 nox , respectively). Human colon cancer cell lines (T84 and Caco2 cells) expressed the Nox1, p22 phox , p51 nox , and Rac1 mRNAs, but not the other NADPH component mRNAs, and secreted only small amounts of O 2 - ( < 2 nmol/mg protein/h). Cotransfection of p41 nox and p51 nox cDNAs in T84 cells enhanced PMA-stimulated O 2 - release 5-fold. Treatment of the transfected T84 cells with recombinant flagellin (rFliC) from Salmonella enteritidis further augmented the O 2 - release in association with the induction of Nox1 protein. The enhanced O 2 - production by cotransfection of p41 nox and p51 nox vectors further augmented the rFliC-stimulated IL-8 release from T84 cells. T84 cells expressed the Toll-like receptor 5, and rFliC rapidly phosphorylated TGF-β-activated kinase 1 and TGF-β-activated kinase 1-binding protein 1. A potent inhibitor for NF-κB (pyrrolidine dithiocarbamate) significantly blocked the rFliC-primed increase in O 2 - production and induction of Nox1 protein. These results suggest that p41 nox and p51 nox are involved in the Nox1 activation in surface mucous cells of the colon, and besides that, epithelial cells discern pathogenicities among bacteria to appropriately operate Nox1 for the host defense.
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Molecular mechanism for activation of superoxide-producing NADPH oxidases.
Takeya R, Sumimoto H
Molecules and cells 16 ( 3 ) 271 - 7 2003.12
Language：Japanese Publishing type：Research paper (scientific journal)
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Fhos, a mammalian formin, directly binds to F-actin via a region N-terminal to the FH1 domain and forms a homotypic complex via the FH2 domain to promote actin fiber formation.
Takeya R, Sumimoto H
Journal of cell science 116 ( Pt 22 ) 4567 - 75 2003.11
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The PB1 domain and the PC motif-containing region are structurally similar protein binding modules.
Yoshinaga S, Kohjima M, Ogura K, Yokochi M, Takeya R, Ito T, Sumimoto H, Inagaki F
The EMBO journal 22 ( 19 ) 4888 - 97 2003.10
Language：Japanese Publishing type：Research paper (scientific journal)
DOI： 10.1093/emboj/cdg475
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Takeya R., Ueno N., Kami K., Taura M., Kohjima M., Izaki T., Nunoi H., Sumimoto H.
Journal of Biological Chemistry 278 ( 27 ) 25234 - 25246 2003.7
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Journal of Biological Chemistry
The catalytic core of a superoxide-producing NADPH oxidase (Nox) in phagocytes is gp91 phox /Nox2, a membrane-integrated protein that forms a heterodimer with p22 phox to constitute flavocytochrome b 558 . The cytochrome becomes activated by interacting with the adaptor proteins p47 phox and p67 phox as well as the small GTPase Rac. Here we describe the cloning of human cDNAs for novel proteins homologous to p47 phox and p67 phox , designated p41 nox and p51 nox , respectively; the former is encoded by NOXO1 (Nox organizer 1), and the latter is encoded by NOXA1 (Nox activator 1). The novel homologue p41 nox interacts with p227 phox via the two tandem SH3 domains, as does p47 phox . The protein p51 nox as well as p67 phox can form a complex with p47 phox and with p41 nox via the C-terminal SH3 domain and binds to GTP-bound Rac via the N-terminal domain containing four tetratricopeptide repeat motifs. These bindings seem to play important roles, since p47 phox and p67 phox activate the phagocyte oxidase via the same interactions. Indeed, p41 nox and p51 nox are capable of replacing the corresponding classical homologue in activation of gp91 phox . Nox1, a homologue of gp91 phox , also can be activated in cells, when it is coexpressed with p41 nox and p51 nox , with p41 nox and p67 phox , or with p47 phox and p51 nox ; in the former two cases, Nox1 is partially activated without any stimulants added, suggesting that p41 nox is normally in an active state. Thus, the novel homologues p41 nox and p51 nox likely function together or in combination with a classical one, thereby activating the two Nox family oxidases.
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Phosphorylation of p47phox directs phox homology domain from SH3 domain toward phosphoinositides, leading to phagocyte NADPH oxidase activation.
Ago T, Kuribayashi F, Hiroaki H, Takeya R, Ito T, Kohda D, Sumimoto H
Proceedings of the National Academy of Sciences of the United States of America 100 ( 8 ) 4474 - 9 2003.4
Language：Japanese Publishing type：Research paper (scientific journal)
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PAR3beta, a novel homologue of the cell polarity protein PAR3, localizes to tight junctions.
Kohjima M, Noda Y, Takeya R, Saito N, Takeuchi K, Sumimoto H
Biochemical and biophysical research communications 299 ( 4 ) 641 - 6 2002.12
Language：Japanese Publishing type：Research paper (scientific journal)
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PAR3β, a novel homologue of the cell polarity protein PAR3, localizes to tight junctions
Kohjima M., Noda Y., Takeya R., Saito N., Takeuchi K., Sumimoto H.
Biochemical and Biophysical Research Communications 299 ( 4 ) 641 - 646 2002.12
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Biochemical and Biophysical Research Communications
The cell polarity protein PAR3, conserved from the nematode to the vertebrate, forms a complex with PAR6 and atypical protein kinase C (aPKC), and the protein complex occurs at the tight junctions in mammalian epithelial cells. Here we have cloned human cDNA for a novel PAR3 homologue, designated PAR3β, whose messages are present in a variety of tissues and most abundantly expressed in the adult and fetal kidneys. The encoded protein of 1205 amino acids contains a region homologous to the aPKC-binding domain of PAR3α, another human homologue previously identified, and three PDZ domains; the first PDZ domain of PAR3α is considered to interact with PAR6. Unexpectedly, in contrast to other PAR3s found in various species, PAR3β is incapable of binding to any isotypes of PAR6 or aPKC. Nevertheless PAR3β, expressed intrinsically or extrinsically, localizes to the tight junctions, indicating that the localization does not require the ternary complex formation. © 2002 Elsevier Science (USA). All rights reserved.
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Nox4, a novel homologue of the phagocyte NADPH oxidase catalytic subunit gp91<sup>phox</sup>
Shiose A., Kuribayashi F., Takeya R., Sumimoto H.
International Congress Series 1233 ( C ) 63 - 68 2002.11
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：International Congress Series
During phagocytosis, the NADPH oxidase in neutrophils produces superoxide, a precursor of microbicidal oxidants, thereby playing a crucial role in host defense. The phagocyte oxidase contains the two subunits p22 phox and gp91 phox , the latter of which contains binding sites for the heme, FAD, and NADPH, forming the complete electron-transporting apparatus. Recent studies have revealed that four nonphagocytic homologues of gp91 phox exist, including Nox4, whose cDNA we have currently cloned. Here we describe the molecular nature of Nox4, in comparison with those of other members of the NAD(P)H oxidase family. © 2002 Elsevier Science B.V.
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Diverse recognition of non-PxxP peptide ligands by the SH3 domains from p67(phox), Grb2 and Pex13p.
Kami K, Takeya R, Sumimoto H, Kohda D
The EMBO journal 21 ( 16 ) 4268 - 76 2002.8
Language：Japanese Publishing type：Research paper (scientific journal)
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Kami K., Takeya R., Sumimoto H., Kohda D.
EMBO Journal 21 ( 16 ) 4268 - 4276 2002.8
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：EMBO Journal
The basic function of the Src homology 3 (SH3) domain is considered to be binding to proline-rich sequences containing a PxxP motif. Recently, many SH3 domains, including those from Grb2 and Pex13p, were reported to bind sequences lacking a PxxP motif. We report here that the 22 residue peptide lacking a PxxP motif, derived from p47 phox , binds to the C-terminal SH3 domain from p67 phox . We applied the NMR cross-saturation method to locate the interaction sites for the non-PxxP peptides on their cognate SH3 domains from p67 phox , Grb2 and Pex13p. The binding site of the Grb2 SH3 partially overlapped the conventional PxxP-binding site, whereas those of p67 phox and Pex13p SH3s are located in different surface regions. The non-PxxP peptide from p47 phox binds to the p67 phox SH3 more tightly when it extends to the N-terminus to include a typical PxxP motif, which enabled the structure determination of the complex, to reveal that the non-PxxP peptide segment interacted with the p67 phox SH3 in a compact helix-turn-helix structure (PDB entry 1K4U).
DOI： 10.1093/emboj/cdf428
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Nox4, a novel homologue of the phagocyte NADPH oxidase catalytic subunit gp91phox
Shiose A, Kuribayashi F, Takeya R, Sumimoto H
Int. Congr. Ser 1233 63 - 68 2002
Language：English Publishing type：Research paper (scientific journal)
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The PX domain as a novel phosphoinositide-binding module
Ago T., Takeya R., Hiroaki H., Kuribayashi F., Ito T., Kohda D., Sumimoto H.
Biochemical and Biophysical Research Communications 287 ( 3 ) 733 - 738 2001.9
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Biochemical and Biophysical Research Communications
The phox (phagocyte oxidase) homology (PX) domain occurs in the mammalian phox proteins p40 phox and p47 phox , the polarity establishment protein Bem1p in budding yeast, and a variety of proteins involved in membrane trafficking. Here we show that the PX domains of p40 phox and p47 phox directly bind to phosphoinositides: p40 phox prefers Ptdlns(3)P, while p47 phox does Ptdlns(4)P and Ptdlns(3,4)P 2 . In addition, the Bem1p PX domain also interacts with Ptdlns(4)P. When the p40 phox PX domain is expressed as a fusion to green fluorescent protein in HeLa cells, it exists at early endosomes where Ptdlns(3)P is enriched. Furthermore, a mutant p40 phox PX carrying the substitution of Lys for Arg105 only weakly binds to phosphoinositides in vitro, and fails to locate to early endosomes. Thus the PX domain functions as a novel phosphoinositide-binding module and likely participates in targeting of proteins to membranes. © 2001 Academic Press.
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Noda Y., Takeya R., Ohno S., Naito S., Ito T., Sumimoto H.
Genes to Cells 6 ( 2 ) 107 - 119 2001.4
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Genes to Cells
Background: Asymmetric cell division in the Caenorhabditis elegans embryos requires products of par (partitioning defective) genes 1-6 and atypical protein kinase C (aPKC), whereas Cdc42 and Rac, members of the Rho family GTPases, play an essential role in cell polarity establishment in yeast and mammalian cells. However, little is known about a link between PAR proteins and the GTPases in cell polarization. Results: Here we have cloned cDNAs for three human homologues of PAR6, designated PAR6α, β and γ, comprising 345, 372 and 376 amino acids, respectively. The PAR6 proteins harbour a PDZ domain and a CRIB-like motif, and directly interact with GTP-bound Rac and Cdc42 via this motif and with the aPKC isoforms PKCι/λ and PKCζ via the N-terminal head-to-head association. These interactions are not mutually exclusive, thereby allowing the PAR6 proteins to form a ternary complex with the GTPases and aPKC, both in vitro and in vivo. When PAR6 and aPKC are expressed with a constitutively active form of Rac in HeLa or COS-7 cells, these proteins co-localize to membrane ruffles, which are known to occur at the leading edge of polarized cells during cell movement. Conclusion: Human PAR6 homologues most likely play an important role in the cell polarization of mammalian cells, by functioning as an adaptor protein that links activated Rac and Cdc42 to aPKC signalling.
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The PX domain as a novel phosphoinositide- binding module.
Ago T, Takeya R, Hiroaki H, Kuribayashi F, Ito T, Kohda D, and Sumimoto H
Biochem. Biophys. Res. Commun. 287 733 - 738 2001
Language：English Publishing type：Research paper (scientific journal)
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Human homologues of the Caenorhabditis elegans cell polarity protein PAR6 as an adaptor that links the small GTPases Rac and Cdc42 to atypical protein kinase C.
Noda Y, Takeya R, Ohno S, Naito S, Ito T, and Sumimoto H
Genes Cells 6 107 - 119 2001
Language：English Publishing type：Research paper (scientific journal)
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A novel intracellular membrane-bound calcium-independent phospholipase A<inf>2</inf>
Tanaka H., Takeya R., Sumimoto H.
Biochemical and Biophysical Research Communications 272 ( 2 ) 320 - 326 2000.6
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Biochemical and Biophysical Research Communications
We have cloned human cDNA encoding a novel protein of 782 amino acids that contains the lipase consensus sequence Gly-Xaa-Ser-Xaa-Gly and several stretches surrounding the motif, which are homologous to those of the catalytic domain of cytosolic calcium-independent phospholipase A 2 (iPLA 2 ). When expressed in COS-7 cells, the protein predominantly exists in the membrane fraction and exhibits a phospholipase A 2 activity in a calcium-independent manner. The transcript of the membrane-bound iPLA 2 gene is ubiquitously observed as a single band of approximately 3.3 kb on Northern blot, with the most abundant expression in the skeletal muscle and heart. By a search of the database, we have also identified its putative C. elegans homologue, which shows 47% identity with that of human in the iPLA 2 catalytic region. Thus the novel type of iPLA 2 is evolutionarily well conserved, suggestive of its biological significance. (C) 2000 Academic Press.
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Interaction of the PDZ domain of human PICK1 with class I ADP-ribosylation factors
Takeya R., Takeshige K., Sumimoto H.
Biochemical and Biophysical Research Communications 267 ( 1 ) 149 - 155 2000.1
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Biochemical and Biophysical Research Communications
We have cloned the cDNA encoding human PICK1 (protein interacting with C kinase 1), a PDZ domain-containing protein of 415 amino acids, and also identified the Drosophila homologue by search of the databank. Northern blot analysis shows a single mRNA of about 2.0 kb ubiquitously expressed in human tissues. Although PICK1 proteins harbor a region homologous to arfaptin1 and arfaptin2, two proteins that bind to the ARF (ADP-ribosylation factor), this region of PICK1 does not interact with ARFs in the yeast two-hybrid system. On the other hand, the PDZ domain of PICK1 is capable of interacting with constitutively active, GTP-bound forms of ARF1 and ARF3, but neither with those of ARF5/6 nor with the GDP-bound ARFs. The PICK1-ARF interaction is abrogated by introduction of mutations in the PDZ domain or by deletion of the extreme C-terminus of ARF1. Thus, PICK1 specifically interacts with ARF1/3 in the GTP-bound state, suggesting that PICK1 participates in ARF1/3-mediated cellular processes. (C) 2000 Academic Press.
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A novel intracellular membrane-bound calcium-independent phospholipase A2.
Tanaka H., Takeya R, Sumimoto H
Biochem. Biophys. Res. Commun. 272 320 - 326 2000
Language：English Publishing type：Research paper (scientific journal)
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Interaction of the PDZ domain of human PICK1 with class I ADP-ribosylation factors.
Takeya R, Takeshige K, Sumimoto H
Biochem. Biophys. Res. Commun. 267 149 - 155 2000
Language：English Publishing type：Research paper (scientific journal)
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Izuhara K., Arinobu Y., Sumimoto H., Nunoi H., Takeya R., Higuchi K., Takeshige K., Hamasaki N., Harada N.
Molecular Immunology 36 ( 1 ) 45 - 52 1999.1
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Molecular Immunology
Interleukin (IL)-4 plays an important role in IgE synthesis in B cells and in Th2 differentiation in T cells, IL-4 conducts its biological activities through binding to the IL-4 receptor (IL-4R) on the surface of target cells. IL-4R are thought to be composed of the IL-4R α chain (IL- 4Rα) and either the IL-2R γ chain or the IL-13R α chain. We have previously shown that the membrane-proximal portion in the cytoplasmic domain of the human IL-4Rα (hIL-4Rα) is critical for proliferation, generation of germline ε transcript, and activation of STAT6, based on analyses of truncated hIL-4Rαs. In this study, we found that p47p(phox), an activator of the phagocyte NADPH oxidase, binds to this portion by the two-hybrid system. Furthermore, we observed the association of p47(phox) with the hIL-4Rα in B cells derived from a normal donor. These results suggest that p47(phox) is involved in the signal transduction of IL-4 in B cells. However, activation of STAT6, CD23 expression, and IgE synthesis induced by IL-4 were not affected in p47(phox)-deficient patients, which raises the possibility that p47(phox) may be important in other signaling activities as well in B cells.
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Association of the interleukin-4 receptor a chain with p47phox, an activator of the phagocyte NADPH oxidase in B cells.
Izuhara K*, Arinobu Y, Sumimoto H, Nunoi H, Takeya R, Higuchi K, Takeshige K, Hamasaki N, Harada N.
Mol. Immunol. 36 45 - 52 1999
Language：English Publishing type：Research paper (scientific journal)