| 高 靖（がお じん） | データ更新日：2023.11.28 |
助教 ／
歯学研究院
歯学部門
口腔常態制御学
| 1. | 李傲男、高靖、藤井慎介、清島保、自見英治郎, p130cas plays a crucial role in ER-Golgi network formation for cell differentiation of granular convoluted tubules in mouse submandibular glands., 第 64 回歯科基礎医学会学術大会, 2022.09, [URL]. |
| 2. | 黄菲、高靖、李傲男、溝上顕子、自見英治郎, The regulatory mechanism of NF-kB signals involved in postmenopausal osteoporosis and weight gain., 第 64 回歯科基礎医学会学術大会, 2022.09, [URL]. |
| 3. | 高 靖 , 李傲男, 藤井 慎介, 清島 保, 自見 英治郎, マウス唾液腺の機能発現におけるp130Casの役割, 第94回日本生化学会大会, 2021.11. |
| 4. | ＃李傲男、高靖、藤井慎介、清島保、自見英治郎 , p130Cas はマウス顎下腺の顆粒性導管の発達に関与する, 第63回歯科基礎医学会学術大会, 2021.10. |
| 5. | 黄菲、高靖、自見英治郎, NF-κB，p65 の 534 番目のリン酸化は閉経後骨粗鬆症と体重増加に関与する, 第63回歯科基礎医学会学術大会, 2021.10. |
| 6. | ＃井上茜、 高靖、吉崎恵悟、＠進正史、＠中富千尋、＠中富満城、＠岡部 幸司、＠大島勇人、 高橋一郎 、自見英治郎 , p130Casのエナメル 形成過程における役割, 第６２回歯科基礎医学会学術大会, 2020.09, [URL]. |
| 7. | 室屋 龍佑，高 靖，＠中富 千尋，藤井 慎介，清島 保，自見英治郎, 唾液腺の形態形成及び機能発現における p130Cas の役割, 第６１回歯科基礎医学会学術大会, 2019.10. |
| 8. | 高靖、溝上顕子、＠竹内弘、自見英治郎、＠平田雅人, 脂肪細胞のインスリンシグナリングの調節におけるPRIPの役割, 第４２回日本分子生物学会年会, 2019.12. |
| 9. | Jing Gao, Akiko Mizokami, Hiroshi Takeuchi, Ejiro Jimi and Masato Hirata, A novel molecule involved in the regulation of insulin signaling mediated by internalization of insulin receptor in adipocyte, 第9１回日本生化学会大会, 2018.09, [URL], Insulin resistance is strongly associated with obesity and other symptoms related to the metabolic syndrome (MS). Numerous studies using insulin-resistant animal models and humans have consistently demonstrated a reduced activity of insulin signaling via the insulin receptor substrate (IRS-1)/ Akt pathway, but the molecular mechanism of triggering events remains incompletely understood. We previously reported that PRIP (phospholipase C-related but catalytically inactive protein) interacts with Akt, the center molecule of insulin signaling pathway. In the present study, we investigated whether PRIP is involved in the regulation of insulin signaling. We found that the phosphorylation of of Akt and even upstream molecules, IR (insulin receptor) and IRS-1 (insulin receptor substrate) were inhibited in PRIP-KO (Knockout) MEFs (mouse embryonic fibroblasts), and that glucose uptake was inhibited in adipocytes differentiated from PRIP-KO MEF, indicating insulin insensitivity in PRIP-KO cells. Furthermore, ablation of PRIP diminished the plasma membrane localization of IR in mouse adipocyte. Overexpression of PRIP1 in HepG2 cell blocked the insulin-reduced IR internalization into the cell. PRIP directly interacted with IR and Clathrin Heavy Chain (CLTC) in adipocyte. Silencing of CLTC using siRNA retrieved the plasma membrane localization of IR which was diminished in PRIP-KO adipocyte to the same level of WT cells. These results suggest that PRIP is involved in the regulation of insulin signaling in adipocyte, likely through modulating the internalization of IR.. |
| 10. | ＃室屋 龍佑, 高 靖, ＠中富 千尋, 藤井 慎介, 清島 保, 自見 英治郎 , 唾液腺の発生及び機能発現におけるp130Casの役割, 第６０回歯科基礎医学会学術大会, 2018.09. |
| 11. | 高 靖, 溝上 顕子, 竹内 弘, 自見 英治郎, 平田 雅人, PRIPによる脂肪細胞のインスリンシグナリングの調節, 第６０回歯科基礎医学会学術大会, 2018.09, [URL], 肥満や糖尿病などのメタボリック症候群は世界的な健康問題であるが、特に２型糖尿病の発症基盤の一つであるインスリンシグナル伝達経路異常の分子メカニズムについては、未だ不明な点も多い。イノシトール1,4,5- 三リン酸結合性タンパク質であるPRIP（PLC-Related but catalytically Inactive Protein）はインスリンシグナル伝達経路の中心的分子であるAktと結合する。今回我々はPRIP欠損(KO)マウスを用いて、インスリンシグナリングの調節におけるPRIPの役割について検討を行なった。マウスにインスリン投与後に摘出した脂肪組織のインスリン受容体（IR）とAktのリン酸化レベルを比較すると、KOマウス由来の脂肪組織でIR、Aktともにリン酸化レベルが低下していた。骨格筋と肝臓では差が認められなかった。器官培養した脂肪組織をインスリン刺激すると、KOマウス由来のものでIRおよびAktのリン酸化が抑えられていただけでなく、糖取り込みやGLUT４の細胞膜へのトランスロケーションも抑制されていた。また、KOマウス由来のMEFから分化した脂肪細胞では、IRの膜発現量が野生型と比べて減少していた。インスリンシグナルはIRのクラスリン依存性のエンドサイトーシスにより負に制御される。そこで、脂肪組織を用いて免疫沈降を行ったところPRIPがClathrin Heavy Chain（CLTC）およびIRと結合することがわかった。siRNAを用いてCLTCの発現を抑制すると、KO由来脂肪細胞でIRの膜発現量がWTと同等まで回復した。以上の結果から、PRIPはIRのエンドサイトーシスの調節を介してIRの膜発現量を調節し、脂肪細胞におけるインスリンシグナルを制御していることが示唆された。. |
| 12. | Jing Gao, Akiko Mizokami, Hiroshi Takeuchi, Ejiro Jimi and Masato Hirata, インスリン受容体基質のリン酸化制御におけるPRIPの役割, 2017年度生命科学系学会合同年次大会, 2017.12, Numerous studies have demonstrated a reduced activity of insulin signaling, but the molecular mechanism of triggering events remains incompletely understood. We previously reported that PRIP (phospholipase C-related but catalytically inactive protein) interacts with Akt, the center molecule of insulin signaling pathway. In the present study, we investigated whether PRIP is involved in the regulation of insulin signaling. We found that the phosphorylation of of Akt and even upstream molecules, IR (insulin receptor) and IRS-1 (insulin receptor substrate) were inhibited in PRIP-KO (Knockout) MEFs (mouse embryonic fibroblasts), and that glucose uptake was inhibited in adipocytes differentiated from PRIP-KO MEF, indicating insulin insensitivity in PRIP-KO cells. We further examined the serine phosphorylation of IRS-1 which inhibits insulin signaling. We found that insulin triggered more phosphorylation of Ser1101 of IRS-1 in PRIP-KO MEF than WT, and that dephosphorylation process of Ser1101 of IRS-1 was blocked by calyculin A, an inhibitor for the protein phosphatase1 (PP1) and 2A (PP2A). Furthermore, we detected the interaction of IRS-1 and PP2A catalytic subunit (PP2Ac) using in situ Proximity Ligation Assay (PLA) in WT MEF cells, which was diminished in PRIP-KO cells. Combined with our previous finding that PRIP binds to PP2Ac, we speculate that serine phosphorylation of IRS was enhanced due to the decreased dephosphorylation process in PRIP-KO MEF, which in turn inhibited insulin signaling. These results suggest that PRIP is involved in the regulation of insulin signaling, likely through modulating serine phosphorylation of IRS-1.. |
| 13. | Jing Gao, Akiko Mizokami, Masato Hirata, Phospholipase C-related but Catalytically Inactive Protein, PRIP is involved in the regulation of insulin signaling via IRS-1/Akt pathway by modulating serine phosphorylation of IRS-1, 2016 American Society for Cell Biology Annual Meeting, 2016.12, [URL], Insulin resistance is strongly associated with obesity and other symptoms related to the metabolic syndrome (MS). Numerous studies using insulin-resistant animal models and humans have consistently demonstrated a reduced activity of insulin signaling via the insulin receptor substrate (IRS-1)/phosphatidylinositol (PI) 3-kinase/Akt pathway, but the molecular mechanism of triggering events remains incompletely understood. We previously reported that PRIP (phospholipase C-related but catalytically inactive protein) interacts with Akt, the center molecule of insulin signaling pathway. In the present study, we investigated whether PRIP is involved in the regulation of insulin signaling using mouse embryonic fibroblasts (MEF) from wild type (WT) and PRIP-Knockout (KO) mice. We found that the phosphorylation of Thr308 and Ser473 of Akt and tyrosine phosphorylation of even upstream molecules, IR (insulin receptor) and IRS-1 (insulin receptor substrate-1) were inhibited in MEF cells from PRIP-KO mice, and that glucose uptake was also inhibited in adipocytes differentiated from PRIP-KO MEF, indicating insulin insensitivity in PRIP-KO cells. We then investigated how the insulin signaling via the IR/IRS-1/Akt pathway was inhibited in PRIP-KO MEF cells. Since serine phosphorylation of IRS proteins inhibits insulin signaling, we further examined the serine phosphorylation of IRS-1 using MEF cells. We found that stimulation of PRIP-KO MEF with insulin for 30 min triggered more phosphorylation of Ser1101 of IRS-1 than WT, and that the dephosphorylation process of Ser1101 of IRS-1 after insulin stimulation in MEF cells from WT mice was blocked by calyculin A, an inhibitor for the protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A). Furthermore, we detected the interaction of IRS-1 and protein phosphatase 2A catalytic subunit (PP2Ac), but not PP1 and PP2A subunit A using in situ Proximity Ligation Assay (PLA) in WT MEF cells, whereas PLA signals was dramatically diminished in PRIP-KO cells. Based on these results and our previous finding that PRIP binds with PP2Ac, we speculated that serine phosphorylation of IRS-1 was enhanced due to the decreased dephosphorylation process in PRIP-KO MEF cells compared to WT cells, which in turn inhibited the IRS-1/PI3K/Akt insulin signaling. Collectively, these results suggest that PRIP is involved in the regulation of insulin signaling, likely through modulating the serine phosphorylation of IRS-1. . |
| 14. | Jing Gao, Akiko Mizokami, Hiroshi Takeuchi, Masato Hirata, Differential role of SNAP-25 phosphorylation by Protein Kinase A and C in the regulation of SNARE complex formation and exocytosis, The 23rd General Meeting of the Japanese Association for Dental Science, 2016.10, [URL], We studied the functional consequences of SNAP-25 phosphorylation by protein kinase A (PKA) and protein kinase C (PKC). Phosphorylation of SNAP-25 at Thr138 by PKA inhibited SNARE complex formation and functional exocytosis in PC12 cells. Phosphorylation of SNAP-25 at Ser187 by PKC enhanced SNARE complex formation and functional exocytosis in PC12 cells. . |
| 15. | Jing Gao, 平田牧子, 溝上 顕子, 竹内 弘, 平田 雅人, SNARE複合体形成と開口分泌調節におけるSNAP-25リン酸化の役割, 第５８回歯科基礎医学会学術大会, 2016.08, [URL], SNARE 複合体は syntaxin、SNAP-25 、VAMPよりなるが、それらのタンパク質のリン酸化によって開口分泌は調節される。PKA および PKC による SNAP-25 のリン酸化による調節はよく知られているが、リン酸化された SNAP-25 の SNARE 複合体の形成における役割は明らかではない。そこで、本研究では、SNAP-25 の PKA および PKC によるリン酸化の SNARE 複合体の形成に及ぼす影響を検討した。精製した SNAP-25、syntaxin-1、VAMP-2 を用いた実験の結果、in vitro において SNARE 複合体の形成は PKA による SNAP-25 の Thr138 のリン酸化によって抑えられ、PKC による Ser187 のリン酸化によって促進された。また、PC12 細胞における SNARE 複合体形成は PKA 活性化剤であるホルスコリン刺激によって阻害され、PKC の活性化剤であるPMA によって促進された。高カリウムイオン刺激による PC12 からのノルアドレナリン分泌は、ホルスコリン、PMA いずれの刺激によっても増加した。SNAP-25 を欠損させた PC12 細胞では高濃度カリウムイオン刺激によるノルアドレナリン分泌は抑制されたが、そこに野生型 SNAP-25 の遺伝子を導入するとノルアドレナリン分泌能が回復した。SNAP-25 を欠損させた PC12 細胞に SNAP-25 のリン酸化されない変異体である T138A または S187A 変異体を発現させても高濃度カリウムイオン刺激による分泌応答は回復したが、ホルスコリン刺激による分泌増強は野生型 SNAP-25 を発現させたものと比べて T138A 変異体を発現させた細胞においてより明白に認められた。一方、S187A を発現させた細胞における PMA の効果は野生型を発現させたものと比べて抑えられていた。以上のことから、PKA および PKC による SNAP-25 のリン酸化は SNARE 複合体の形成を、それぞれ抑制的、あるいは促進的に調節し、PC12 細胞における開口分泌を効果的に調節していることが示唆された。 . |
| 16. | Aya Nishikawa, Jing Gao, Akiko Mizokami, Makiko Hirata, Masato Hirata, Involvement of Phospholipase C-related but Catalytically Inactive Protein, PRIP in the Regulation of Insulin Signaling , The 9th KOREA-JAPAN Conference on Cellular Signaling for Young Scientists , 2016.07. |
| 17. | Jing Gao, Makiko Hirata, 溝上 顕子, 髙橋 一郎, 竹内 弘, 平田 雅人, Differential roles of SNAP-25 phosphorylation by protein kinase A and C in the regulation of SNARE complex formation and exocytosis in PC12 cells, 第３８回日本分子生物学会年会・第８８回日本生化学会大会合同大会, 2015.12, [URL]. |
| 18. | Jing Gao, 竹内 弘, 平田 雅人, SNAP-25 Phosphorylation by Protein Kinase-A and -C is Differentially Involved Exocytosis through the Regulation of SNARE Complex Formation, 平成２７年度日本生化学会九州支部例会, 2015.05. |
| 19. | Masato Hirata, Goro Sugiyama, Jing Gao, Hiroshi Takeuchi, Phopholipase C-related but catalytically inactive protein, PRIP as a scaffolding protein for phospho-regulation. , The 39th European Symposium on Hormones and Cell Regulation., 2014.10. |
| 20. | Jing Gao, Hiroshi Takeuchi, Daguang Wang, Masato Hirata, Phosphorylation of SNAP-25 by protein kinase-A is negatively involved in calcium-dependent exocytosis in PC12 cells , 第８７回日本生化学会大会, 2014.10. |
| 21. | Jing Gao, Hiroshi Takeuchi, Daguang Wang, Masato Hirata, Differential Role of SNAP-25 phosphorylation by protein kinase-A and –C in SNARE complex formation, 第８６回日本生化学大会, 2013.09, [URL]. |
| 22. | Jing Gao, Hiroshi Takeuchi, Masato Hirata, Phospho-dependent Regulation of Exocytosis, 先端歯学スクール２０１３, 2013.09. |
| 23. | Koki Nagano, Hiroshi Takeuchi, Jing Gao, Takahito Otani, Masato Hirata, Phosphorylation of tomosyn by Akt is implicated in the regulation of GLUT4 translocation, The 8th Japan-Korea Conference on Cellular Signaling for Young Scientists, 2013.11. |
| 24. | Akiko Mizokami, Yu Yasutake, Jing Gao, Hiroshi Takeuchi, Masato Hirata, Osteocalcin induces release of glucagon-like peptide-1 and improves metabolic state in mice, The 8th Japan-Korea Conference on Cellular Signaling for Young Scientists, 2013.11. |
| 25. | Masato Hirata, Goro Sugiyama, Jing Gao, Hiroshi Takeuchi, Phospholipase C-related but catalytically inactive protein, PRIP as a scaffolding protein for phospho-regulation., International Symposium on PI-PLC Activity and Signaling , 2013.07. |
| 26. | Jing Gao, Hiroshi Takeuchi, Zhao Zhang, Daguang Wang, Masato Hirata, SNAP-25 phosphorylation causes down-regulation of SNARE complex formation., 第８５回日本生化学会大会, 2012.12, [URL]. |
| 27. | Jing Gao, Hiroshi Takeuchi, zhao zhang, Daguang Wang, Masato Hirata, Role of SNAP-25 phosphorylation by protein kinase A in SNARE complex formation., The 22nd IUBMB & 37th FEBS Congress, 2012.09, [URL]. |
| 28. | Jing Gao, Hiroshi Takeuchi, Zhao Zhang, Goro Sugiyama, Koki Nagano and Masato Hirata, Roles of PRIP in phospho-regulation of exocytosis through the interaction with protein phosphatases, The 7th Korea-Japan Conference on Cellular Signaling for Young Scientist, 2012.02. |
| 29. | Jing Gao, Hiroshi Takeuchi, Zhao Zhang, Goro Sugiyama, Koki Nagano, Masato Hirata, Phospho-dependent modulation of exocytosis by PRIP, The 10th JBS Biofrontier Symposium on New Aspects of Phospholipid Biology and Medicine, 2011.11, [URL]. |
| 30. | Jing Gao, Hiroshi Takeuchi, Zhao Zhang, Goro Sugiyama, Masato Hirata, Involvement of PRIP in Exocytosis through phospho-dependent regulation of SNAP-25 , 第８４回日本生化学会大会, 2011.09, [URL]. |
| 31. | Gao Jing, Takeuchi Hiroshi, Zhang Zhao and Hirata Masato., Regulatory role of PRIP in exocytosis through the interaction with protein phosphatase., The 12th IUBMB, 21st FAOBMB &ComBio2010 Conferences, 2010.09, [URL]. |
| 32. | Gao Jing, Takeuchi Hiroshi, Zhang ZHao, Hirata Masato., Implication of PRIP in phospho-denpendent regulation of exocytosis. , 第３３回日本分子生物学会年会・第８３回日本生化学会大会合同大会, 2010.12, [URL]. |
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