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jing gao Last modified date：2023.06.26

Assistant Professor / Oral Biological Sciences
Department of Dental Science
Faculty of Dental Science




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Homepage
https://kyushu-u.pure.elsevier.com/en/persons/jing-gao
　Reseacher Profiling Tool　Kyushu University Pure
Phone
092-642-6321
Fax
092-642-6322
Academic Degree
Ph.D
Field of Specialization
biochemistry, cellular biology, molecular biology
Research
Research Interests
  • Role of PRIP in regulation of insulin signaling
    keyword : insulin signaling, insulin resistance,
    2015.04～2019.03.
  • Phospho-regulation of exocytosis by protein complex formation
    keyword : SNARE, exocytosis, phosphorylation
    2013.04～2015.03.
  • Roles of a Novel Molecule in Regulation of Exocytosis
    keyword : exocytosis, membrane lipid, calcium,SNARE complex
    2010.11～2013.03.
Academic Activities
Papers
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1. Gao J., Li A., Fujii S., Huang F., Nakatomi C., Nakamura I., Honda H., Kiyoshima T., Jimi E., p130Cas is required for androgen-dependent postnatal development regulation of submandibular glands., Scientific reports, 10.1038/s41598-023-32390-1., 13, 1, 13(1):5144, 2023.03.
2. Gao J, Mizokami A, Takeuchi H, Li A, Huang F, Nagano H, Kanematsu T, Jimi E, Hirata M., Phospholipase C-related but catalytically inactive protein acts as a positive regulator of insulin signalling in adipocytes, Journal of cell science, 10.1242/jcs.258584., 135, 1, 2022.01.
3. Gao J, Muroya R, Huang F, Nagata K, Shin M, Nagano R, Tajiri Y, Fujii S, Yamaza T, Aoki K, Tamura Y, Inoue M, Chishaki S, Kukita T, Okabe K, Matsuda M, Mori Y, Kiyoshima T, Jimi E., Bone morphogenetic protein induces bone invasion of melanoma by epithelial-mesenchymal transition via the Smad1/5 signaling pathway, Lab Invest., 10.1038/s41374-021-00661-y., 101, 11, 1475-1483, 2021.10.
4. Tatsuki Yaginuma, Jing Gao, Kengo Nagata, Ryusuke Muroya, Huang Fei, Haruki Nagano, Sakura Chishaki, Takuma Matsubara, Shoichiro Kokabu, Kou Matsuo, Tamotsu Kiyoshima, Izumi Yoshioka, Eijiro Jimi, p130Cas Induces Bone Invasion by Oral Squamous Cell Carcinoma by Regulating Tumor Epithelial-Mesenchymal Transition and Cell Proliferation, Carcinogenesis, doi: 10.1093/carcin/bgaa007., 2020.01.
5. Akiko Mizokami, Satoru Mukai, Jing Gao, Tomoyo Kawakubo-Yasukochi, Takahito Otani, Hiroshi Takeuchi, Eijiro Jimi, Masato Hirata, GLP-1 Signaling Is Required for Improvement of Glucose Tolerance by Osteocalcin, the Journal of endocrinology , 10.1530/JOE-19-0288, Vol 244, 2, 2019.11.
6. Satoshi Asano, Yuri Taniguchi, Yosuke Yamawaki, Jing Gao, Kae Harada , Hiroshi Takeuchi, Masato Hirata, Takashi Kanematsu, Suppression of cell migration by phospholipase C-related catalytically inactive protein-dependent modulation of PI3K signalling., Scientific Reports, 10.1038/s41598-017-05908-7, 7, 1, 2017.07, [URL], The metabolic processes of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] into PI(3,4,5)P3 and the subsequent PI(3,4,5)P3 signalling are involved in cell migration. Dysfunctions in the control of this pathway can cause human cancer cell migration and metastatic growth. Here we investigated whether phospholipase C-related catalytically inactive protein (PRIP), a PI(4,5)P2-binding protein, regulates cancer cell migration. PRIP overexpression in MCF-7 and BT-549 human breast cancer cells inhibited cell migration in vitro and metastasis development in vivo. Overexpression of the PRIP pleckstrin homology domain, a PI(4,5)P2 binding motif, in MCF-7 cells caused significant suppression of cell migration. Consistent with these results, in comparison with wild-type cells, Prip-deficient mouse embryonic fibroblasts exhibited increased cell migration, and this was significantly attenuated upon transfection with a siRNA targeting p110α, a catalytic subunit of class I phosphoinositide 3-kinases (PI3Ks). PI(3,4,5)P3 production was decreased in Prip-overexpressing MCF-7 and BT-549 cells. PI3K binding to PI(4,5)P2 was significantly inhibited by recombinant PRIP in vitro, and thus the activity of PI3K was downregulated. Collectively, PRIP regulates the production of PI(3,4,5)P3 from PI(4,5)P2 by PI3K, and the suppressor activity of PRIP in PI(4,5)P2 metabolism regulates the tumour migration, suggesting PRIP as a promising target for protection against metastatic progression..
7. Koki Nagano, Hiroshi Takeuchi, Jing Gao, Yoshihide Mori, Takahito Otani, Daguang Wang, Hirata Masato, Tomosyn is a novel Akt substrate mediating insulin-dependent GLUT4 exocytosis, INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY, 10.1016/j.biocel.2015.02.013, 62, 62-71, 2015.05.
8. Daguang Wang, Hiroshi Takeuchi, Jing Gao, Zhao Zhang, Masato Hirata, Hetero-oligomerization of C2 domains of phospholipase C-related but catalytically inactive protein and synaptotagmin-1, Advances in Biological Regulation, 10.1016/j.jbior.2014.09.001., 2015.01, The C2 domain is a protein module often found in molecules that regulate exocytosis. C2 domains mediate interactions between the parental molecule and Ca2+, phospholipids, and proteins. Although various molecules have been shown to interact with several C2 domains, no interactions between the C2 domains from different molecules have yet been reported. In the present study, we identified direct interactions between the C2 domain of PRIP (phospholipase C-related but catalytically inactive protein) and the C2 domains of other molecules. Among the C2 domains examined, those of synaptotagmin-1 (Syt1-C2A and Syt1-C2B) and phospholipase C δ-1 bound to the C2 domain of PRIP. We investigated the interactions between the C2 domain of PRIP (PRIP-C2) with Syt1-C2A and Syt1-C2B, and the mode of binding of each was Ca2+-dependent and -independent, respectively. We further demonstrated that the Ca2+ dependence of the interaction between PRIP-C2 and Syt1-C2A was attributed to Ca2+ binding with Syt1-C2A, but not PRIP-C2, using a series of mutants prepared from both C2 domains. We previously reported that the interaction between PRIP-C2 and the membrane fusion machinery suggested a critical role for PRIP in exocytosis; therefore, the results of the present study further support the importance of PRIP-C2 in the inhibitory function of PRIP in regulating exocytosis..
9. Goro Sugiyama, Hiroshi Takeuchi, Takashi Kanematsu, Jing Gao, Miho Matsuda, Masato Hirata, Phospholipase C-related but catalytically inactive protein, PRIP as a scaffolding protein for phospho-regulation, Advanced in Biological Regulation, 10.1016/j.jbior.2013.07.001, 53, 3, 331-340, 2013.07.
10. Zhao Zhang, Hiroshi Takeuchi, Jing Gao, Daguang Wang, DeclanJ. James, Thomas F.J.Martin, Masato Hirata, PRIP (Phospholipase C-related but Catalytically Inactive Protein) inhibits exocytosis by direct interactions with Syntaxin 1 and SNAP-25 through its C2 domain, The Journal of Biological Chemistry, 10.1074/jbc.M112.419317, 288, 11, 7769-7780, 2013.03.
11. Akiko Mizokami, Yu Yasutake, JingGao, Miho Matsuda, Ichiro Takahashi, Hiroshi Takeuchi, Masato Hirata, Osteocalcin induces release of glucagon-like peptide-1 and thereby stimulates insulin secretion in mice, Plos One, 10.1371/journal.pone.0057375, 8, 2, e57375, 2013.02.
12. Jing Gao, Hiroshi Takeuchi, Zhao Zhang, Mitsunori Fukuda, Masato Hirata, Phospholipase C-related but catalytically inactive protein (PRIP) modulates synaptosomal-associated protein 25 (SNAP-25) phosphorylation and exocytosis., The Journal of Biological Chemistry, 10.1074/jbc.M111.294645, 287, 13, 10565-10578, 2012.03, [URL], Exocytosis is one of the most fundamental cellular events. The basic mechanism of the final step, membrane fusion, is mediated by the formation of the SNARE complex, which is modulated by the phosphorylation of proteins controlled by the concerted actions of protein kinases and phosphatases. We have previously shown that a protein phosphatase-1 (PP1) anchoring protein, phospholipase C-related but catalytically inactive protein (PRIP), has an inhibitory role in regulated exocytosis. The current study investigated the involvement of PRIP in the phospho-dependent modulation of exocytosis. Dephosphorylation of synaptosome-associated protein of 25 kDa (SNAP-25) was mainly catalyzed by PP1, and the process was modulated by wild-type PRIP but not by the mutant (F97A) lacking PP1 binding ability in in vitro studies.We then examined the role of PRIP in phospho-dependent regulation of exocytosis in cell-based studies using pheochromocytoma cell line PC12 cells, which secrete noradrenalin. Exogenous expression of PRIP accelerated the dephosphorylation process of phosphorylated SNAP-25 after for-skolin or phorbol ester treatment of the cells. The phospho-states of SNAP-25 were correlated with noradrenalin secretion, which was enhanced by forskolin or phorbol ester treatment and modulated by PRIP expression in PC12 cells. Both SNAP-25 and PP1 were co-precipitated in anti-PRIP immunocomplex isolated from PC12 cells expressing PRIP. Collectively, together with our previous observation regarding the roles of PRIP in PP1 regulation, these results suggest that PRIP is involved in the regulation of the phospho-states ofSNAP-25by modulating the activity of PP1, thus regulating exocytosis..
13. Gao, J., Takeuchi, H., Umebayashi, H., Zhang, Z., Matsuda, M. and Hirata, M., Assay of dense-core vesicle exocytosis in permeabilized PC12 cells, Andvances in Enzyme Regulation, 50, 237-246, 2010.01.
14. Takeuchi, H., Takeuchi, T., Gao, J., Cantley, LC. and Hirata, M., Characterization of PXK as a protein involved in epidermal growth factor receptor trafficking., Molecular and Cellular Biology, 30, 7, 1689-1702, 2010.04, The phox homology (PX) domain is a phosphoinositide-binding module that typically binds phosphatidylinositol 3-phosphate. Out of 47 mammalian proteins containing PX domains, more than 30 are denoted sorting nexins and several of these have been implicated in internalization of cell surface proteins to the endosome, where phosphatidylinositol-3-phosphate is concentrated. Here we investigated a multimodular protein termed PXK, composed of a PX domain, a protein kinase-like domain, and a WASP homology 2 domain. We show that the PX domain of PXK localizes this protein to the endosomal membrane via binding to phosphatidylinositol 3-phosphate. PXK expression in COS7 cells accelerated the ligand-induced internalization and degradation of epidermal growth factor receptors by a mechanism requiring phosphatidylinositol 3-phosphate binding but not involving the WASP homology 2 domain. Conversely, depletion of PXK using RNA interference decreased the rate of epidermal growth factor receptor internalization and degradation. Ubiquitination of epidermal growth factor receptor by the ligand stimulation was enhanced in PXK-expressing cells. These results indicate that PXK plays a critical role in epidermal growth factor receptor trafficking through modulating ligand-induced ubiquitination of the receptor..
15. Gao, J., Takeuchi, H., Zhang, Z., Fujii, M., Kanematsu, T. and Hirata, M., Binding of phospholipase C-related but catalytically inactive protein to phosphatidylinositol 4,5-bisphosphate via the PH domain., Cellular Signalling, 21, 1180-1186, 2009.03, A well-known protein module regulating molecular interactions is the pleckstrin homology (PH) domain whose best-characterised ligand is phosphoinositide. In the present study, we analysed the PH domain from PRIP (phospholipase C-related but catalytically inactive protein, comprising types 1 and 2) regarding phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] binding employing a variety of binding assays. The PH domains prepared from PRIP-1 and -2 showed similar binding profiles to soluble ligands in vitro and showed similar plasma membrane localisation to that of PLC-δ1; however, the PH domain with the N-terminal extension of PRIP-1 but not PRIP-2 showed even distribution throughout the cytoplasm, indicating that the N-terminal extension of PRIP-1 inhibited binding to PtdIns(4,5)P2 present in the plasma membrane. A chimeric molecule of PLC-δ1 PH domain with the N-terminal extension of PRIP-1 exhibited similar localisation to PRIP-1 PH domain with the N-terminal extension. Binding assay to liposomes containing various concentrations of PtdIns(4,5)P2 revealed that the PH domain of PLC-δ1 bound steeply to the maximum, even at a concentration of 1.2 mol%, whereas the PH domains from PRIP-1 and -2 bound depending on the concentration up to 5 mol%. We also performed binding experiments using saponin-permeabilised PC12 cells. PH domains from PRIP increased the binding to cells preincubated with the brain cytosol extract in the presence of ATP, during which PtdIns(4,5)P2 were probably synthesised. The binding of PH domain with the following EF hand motifs showed Ca2+-dependent binding. These results indicate that the PH domain of PRIP binds to PtdIns(4,5)P2 present in the plasma membrane, depending on the concentrations of the lipid ligand and Ca2+, suggesting that PRIP might play physiological roles in events involved in the changes of these parameters, probably including Ins(1,4,5)P3..
16. Inoue, R., Matsuki, N., Gao, J., Kanematsu, T. and Hirata, M., The inhibitory effect of alendronate, a nitrogen-containing bisphosphonate on the PI3K/Akt/NFB pathway in osteosarcoma cells., British Journal of Pharmacology, 10.1038/sj.bjp.0706373, 146, 5, 633-641, 2005.11.
Presentations
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1. 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, 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..
2. 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, 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.
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3. 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, 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.
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4. 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.
5. 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.
6. 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.
7. Jing Gao, Hiroshi Takeuchi, Masato Hirata, Phospho-dependent Regulation of Exocytosis, 先端歯学スクール２０１３, 2013.09.
8. 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.
9. 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.
10. Roles of PRIP in phospho-regulation of exocytosis through the interaction with protein phosphatases.
11. Phospho-dependent modulation of exocytosis by PRIP, [URL].
12. The 84th Annual Meeting of the Japanese Biochemical Society , [URL].
13. The 33rd Annual Meeting of the molecular Biology Society of Japan
The 83rd Annual Meeting of the Japanese Biochemical Society.
Membership in Academic Society
  • The Molecular Biology Society of Japan
  • Japansese Association for Oral Biology
  • The Japanese Biochemical Society
  • The Japanese Biochemical Society


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