Attempt of G protein-coupled receptor kinase-interacting proteins involved in engulfment of apoptotic cells and role of the receptor kinase in heart disease

• Project/Area Number: 25670040
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Pharmacology in pharmacy
• Research Institution: Kyushu University
• Principal Investigator: KUROSE HITOSHI 九州大学, 薬学研究科(研究院), 教授 (10183039)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 受容体 / G蛋白質 / 受容体キナーゼ / 貪食 / アポトーシス / 心疾患 / TNF-α / NF-κB経路 / BRETプローブ / 細胞内シグナリング / Gタンパク質共役型受容体キナーゼ / GFP

Outline of Final Research Achievements

G protein-coupled receptor kinase 6 (GRK6) is a member of GRK family. GRK6 mediates engulfment of apoptotic cells. In this proposal, molecules upstream or downstream of GRK6 were tried to be identified. FRET or BRET probes to detect conformational changes of GRK6 were made. It would facilitate screening of GRK6-interacting proteins. However, the sensitivities of these probes were too low to detect the interaction with putative GRK6-interacting molecules. Using BRET probe, GRK6 was found to be a mediator of TNF-α-stimulated NF-κB activation. Conformation of GRK6 was changed by TNF-α stimulation, and GRK6 bound and phosphorylated IκB-α leading to NF-κB activation. Thus, GRK6 works as a mediator of TNF-α-induced inflammation.

Research Products

• [Journal Article] GRK6 phosphorylates IκBα at Ser32/Ser36 and enhances TNF-α-induced inflammation via the activation of NF-κB signaling. (2015)
  • Author(s): Ohba Y, Nakaya M, Watari K, Nagasaka A, Kurose H.
  • Journal Title: Biochem Biophys Res Commun. Volume: 460
  • Peer Reviewed
• [Journal Article] GRK6-deficiency in mice causes autoimmune disease due to impaired apoptotic cell clearance. (2013)
  • Author(s): Nakaya M, Tajima M, Kosako H, Nakaya N, 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.
  • Journal Title: Nat. Commun. Volume: 4 Pages: 1532-1532
  • Peer Reviewed
• [Presentation] GRK6 and heart disease (2014)
  • Author(s): Hitoshi Kurose
  • Organizer: FASEB Science Research Conference ~G protein-coupled receptor kinases
  • Place of Presentation: Steamboat Spring, Colorado, USA
  • Year and Date: 2014-06-09 – 2014-06-12
  • Invited
• [Presentation] アポトーシス細胞の貪食におけるGRK6の関与 (2014)
  • Author(s): 仲矢道雄、黒瀬等
  • Organizer: 第87回 日本薬理学会年会
  • Place of Presentation: 仙台国際センター
  • Invited