Role of GRK in engulfment of apoptotic cells
Project/Area Number |
23659043
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Research Category |
Grant-in-Aid for Challenging Exploratory Research
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Allocation Type | Multi-year Fund |
Research Field |
Biological pharmacy
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Research Institution | Kyushu University |
Principal Investigator |
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Project Period (FY) |
2011 – 2012
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Project Status |
Completed (Fiscal Year 2012)
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Budget Amount *help |
¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
|
Keywords | G タンパク質共役型受容体キナーゼ / 細胞内シグナル伝達 / アポトーシス / 自己免疫疾患 / 貪食 / マクロファージ / Gタンパク質共役型受容体キナーゼ / ERMファミリー / 赤血球のリサイクル / 赤脾臓 / 白脾髄 / 受容体キナーゼ |
Research Abstract |
In the body, apoptotic cells are rapidly removed by the cells such as macrophages and dendritic cells. Otherwise, inefficient removal of apoptotic cells results in transition of apoptotic cells to late necrotic cells and leakage of their own intracellular contents. This leakage causes appearance of autoantibody and induction of inflammation, leading to collapse of the body’ s homeostasis. The removal of apoptotic cells is called as engulfment. So far, there are three engulfment pathways: Abl/Abi, ELMO/DOCK180, and ABC/MFGF10/GULF/dynamin signaling pathways. In this study, we revealed that G protein-coupled receptor (GPCR) kinase 6 (GRK6), which is believed to regulate GPCR function, was involved in engulfment. This pathway was independent of three known pathways. GRK6 bound Ezrin/Radixin/Moesin (ERM) and ultimately activated Rac1 that is indispensable for engulfment. GRK6-mediated engulfment was also observed in endogenous macrophages. In GRK6 knockout (GRK6-KO) mice, systemic lupus erythematosus (SLE), one of autoimmune diseases, -like symptoms such as increased anti-double strand DNA antibody in the plasma and deposition of immunocomplex in the kidney were observed. Furthermore, we observed abnormalities in the spleen. In white pulp of the spleen that removes apoptotic B cells, the number of ungulfed apoptotic cells in GRK6-KO mice was higher than that in wild type mice. In red pulp of the spleen that removes aged red blood cells, we observed the increased iron deposition due to impaired removal of aged red blood cells. These results suggest that GRK6 is a mediator of engulf apoptotic cells, and impaired function of GRK6 results in autoimmune disease and affects recycling of red blood cells. This study reveals that GRK has a new role in the cells andbody, although GRK is generally accepted as a mediator of GPCR regulation.
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Report
(3 results)
Research Products
(17 results)
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[Journal Article] GRK6 deficiency in mice causes autoimmune disease due to impaired apoptotic cell clearance2013
Author(s)
Nakaya M, Tajima M, Kosako H, Nakaya T, Hashimoto A, Watari K, Nishihara H, Ohba M, Komiya S, Tani N, Nishida M, Taniguchi H, Sato Y, Matsumoto M, Tsuda M, Kuroda M, Inoue K, Kurose H
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Journal Title
Nature Commun
Volume: 4
Issue: 1
Pages: 1532-1532
DOI
Related Report
Peer Reviewed
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[Journal Article] Attenuated desensitization of b-adrenergic receptor by water-soluble N-nitrosamines that induce S-nitrosylation without NO release2013
Author(s)
Noriko Makita*, Yoji Kabasawa*, Yuko Otani, Firman, Junichiro Sato, Makiko Hashimoto, Michio Nakaya, Hiroaki Nishihara, Masaomi Nangaku, Hitoshi Kurose, Tomohiko Ohwada, Taroh Iiri
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Journal Title
Circ. Res
Volume: 112
Issue: 2
Pages: 327-334
DOI
Related Report
Peer Reviewed
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[Journal Article] Induction of cardiac fibrosis by b-blocker in G protein-independent but GRK5/b-arrestin2-dependent signaling pathways2012
Author(s)
Michio Nakaya, Satsuki Chikura, Kenji Watari, Natsumi Mizuno, Koji Mochinaga, Supachoke Mangmool, Satoru Koyanagi, Shigehiro Ohdo, Yoji Sato, Tomomi Ide, Motohiro Nishida & Hitoshi Kurose
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Journal Title
J. Biol. Chem
Volume: 287
Issue: 42
Pages: 35669-35677
DOI
Related Report
Peer Reviewed
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[Journal Article] Cilostazol Suppresses Angiotensin II-Induced Vasoconstriction via Protein Kinase A-mediated Phosphorylation of the Transient Receptor Potential Canonical 6 Channel.2011
Author(s)
Nishioka K, Nishida N, Ariyoshi M, Jian Z, Saiki S, Hirano M, Nakaya M, Sato Y, Kita S, Iwamoto T, Hirano K, Inoue R, Kurose H.
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Journal Title
Arterioscler. Thromb. Vasc. Biol.
Volume: 31(10)
Pages: 2278-2286
Related Report
Peer Reviewed
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