| Project/Area Number |
11694330
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| Research Category |
Grant-in-Aid for Scientific Research (B).
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Cell biology
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| Research Institution | Osaka University |
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Principal Investigator |
MEKADA Eisuke Research Institute for Microbial Diseases, Osaka University, Professor, 微生物病研究所, 教授 (20135742)
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| Co-Investigator(Kenkyū-buntansha) |
UMADA Toshiyuki Institute of Life Science and Research Center for Innovative Cancer Therapy, Kurume University, Assistant, 分子生命科学研究所, 助手 (30213482)
MIYADO Kenji Research Institute for Microbial Diseases, Osaka University, Assistant, 微生物病研究所, 助手 (60324844)
IWAMOTO Ryo Research Institute for Microbial Diseases, Osaka University, Instructor, 微生物病研究所, 講師 (10213323)
TSUNEOKA Makoto Institute of Life Science and Research Center for Innovative Cancer Therapy, Kurume University, Assistant Professor, 分子生命科学研究所, 助教授 (50197745)
小戝 健一郎 久留米大学, 医学部, 助手 (90258418)
山田 源 熊本大学, 動物資源開発センター, 教授 (80174712)
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| Project Period (FY) |
1999 – 2000
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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥6,100,000 (Direct Cost: ¥6,100,000)
Fiscal Year 2000: ¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 1999: ¥3,200,000 (Direct Cost: ¥3,200,000)
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| Keywords | LPA / HB-EGF / Transactivation / G-protein-coupled receptor / Ectodomain shedding / メタロプロデアーゼ / エクトドメインシェディング / リゾフォスファチジン酸 / プロテインキナーゼC / MAPキナーゼキナーゼ |
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| Research Abstract |
The proteolytic piocessing of the extracellular domain, also referred to as ectodomain shedding, is observed in a number of membrane proteins Ectodomain shedding of membrane proteins affects the biological activities of membrane proteins Heparin-binding EGF-like growth factor(HB-EGF)is a member of the epidermal growth factor(EGF)family, and binds to and stimulates the phosphorylation of the EGF receptor. HB-EGF is synthesized as a membrane-anchored precursor protein(pioHB-EGF), but proHB-EGF is cleaved on the cell surface to yield a soluble growth factor. Although secreted mature HB-EGF(sHB-EGF)is a potent mitogen for a number of cell types, proHB-EGF may act as a negative regulator of cell proliferation. Thus, the processing of the juxtamembrane domain of proHB-EGF to sHB-EGF means the conversion of the mode of action of this growth factor from juxtacrine to paracrine, or the switching to an opposite activity for cell growth. Ectodomain shedding of proHB-EGF is induced by a number of stimuli including TPA and calcium ionophore, indicating that this cleavage is a regulated process. However, it is known that a significant amount of the ectodomain is constitutively shed even when cells are cultured in a normal culture medium without any particular stimuli. We revealed that constitutive cleavage as observed in a medium is a kind of stimuli-induced cleavage, mainly due to lysophosphatidic acid(LPA)in the serum. Studies on the signaling cascade downstream of LPA indicated that Ras-Raf-MEK cascade is critical for LPA-induced shedding. Results also indicated that the LPA-induced shedding pathway is distinct from the TPA-induced shedding pathway
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