Analysis of regulation of NDR kinases in mammalian cells

• Project/Area Number: 20790222
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: General medical chemistry
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: NAKAGAWA Kentarou Tokyo Medical and Dental University, 大学院・医歯学総合研究科, 助教 (70451929)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2009: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2008: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: アダプター分子 / リン酸化 / シグナル伝達 / 細胞死 / 細胞内シグナル伝達 / 相乗的活性化

Research Abstract

Mammalian nuclear Dbf2-Related (NDR) kinases (NDR1/2, LATS1/2) play a role in cell proliferation, apoptosis and morphological changes. These kinases are regulated by mammalian sterile 20-like kinases (MSTs) and Mps one binder (MOB) 1. MST2 and MOB1 synergistically activate NDR1. Activated MST2 facilitates the tripartite complex formation of MOB1, MST2 and NDR1 in cells. The in vitro biochemical study demonstrates the phosphorylation of MOB1 by MST2 at several sites. Point mutation analysis revealed that phosphorylation of MOB1 is crucial for the activation of NDR1/2 and LATS1/2. We also demonstrated that MST2 suppressed RASSF6 induced cell death. And at the same time, adaptor protein RASSF6 inhibits MST2 dependent NDR kinase activation.

Research Products

• [Journal Article] c-Jun N-terminal phosphorylatiton antagonizes recruitment of the Mbd3/NuRD repressor complex. (2011)
  • Author(s): Aguilera C, Nakagawa K, Sancho R, Chakraborty A, Hendrich B, Behrens A.
  • Journal Title: Nature 469巻 7329号 Pages: 231-235
  • Peer Reviewed
• [Journal Article] c-Jun N-terminal phosphorylatiton antagonizes recruitment of the Mbd3/NuRD repressor complex. (2011)
  • Author(s): Aguilera, C., et al.
  • Journal Title: Nature Volume: 469 Pages: 231-235
  • Peer Reviewed
• [Journal Article] Filamin associates with stress signalling kinases MKK7 and MKK4 and regulates JNK activation. (2010)
  • Author(s): Nakagawa K, Sugahara M, Yamasaki T, Kajiho H, Takahashi S, Hirayama J, Minami Y, Ohta Y, Watanabe T, Hata Y, Katada T, Nishina H.
  • Journal Title: Biochem.J. 427巻2号 Pages: 237-245
  • Peer Reviewed
• [Journal Article] Filamin associates with stress signalling kinases MKK7 and MKK4 and regulates JNK activation. (2010)
  • Author(s): Nakagawa, K., et al.
  • Journal Title: Biochem.J. Volume: 427 Pages: 237-245
  • Peer Reviewed
• [Journal Article] Blockade by SP600125 of Fcepsilon receptor-induced degranulation and cytokine gene expression in mast cells is mediated through inhibition of phosphatidylinositol 3-kinase signaling pathway. (2009)
  • Author(s): Tanemura S, Momose H, Shimizu N, Kitagawa D, Seo J, Yamasaki T, Nakagawa K, Kajiho H, Penninger JM, Katada T, Nishina H.
  • Journal Title: J.Biochem. 145巻3号 Pages: 345-354
  • Peer Reviewed
• [Journal Article] Roles of mammalian sterile 20-like kinase 2-dependent phosphorylations of Mps one binder 1B in the activation of nuclear Dbf2-related kinases. (2009)
  • Author(s): Bao Y, Sumita K, Kudo T, Withanage K, Nakagawa K, Ikeda M, Ohno K, Wang Y, Hata Y.
  • Journal Title: Genes Cells 14巻12号 Pages: 1369-1381
  • Peer Reviewed
• [Journal Article] Hippo pathway-dependent and -independent roles of RASSF6. (2009)
  • Author(s): Ikeda M, Kawata A, Nishikawa M, Tateishi Y, Yamaguchi M, Nakagawa K, Hirabayashi S, Bao Y, Hidaka S, Hirata Y, Hata Y.
  • Journal Title: Sci.Signal. 2巻90号
  • Peer Reviewed
• [Journal Article] Blockage by SP600125 of Fc{epsilon}Receptor-induced degranulation and cytokine gene expression in mast cells is mediated through inhibition of phosphatidylinositol 3kinase signaling pathway (2009)
  • Author(s): Tanemura, S., et al.
  • Journal Title: J Biochem. 145 Pages: 345-54
  • Peer Reviewed
• [Journal Article] Roles of mammalian sterile 20-like kinase 2-dependent phosphorylations of Mps one binder 1B in the activation of nuclear Dbf2-related kinases (2009)
  • Author(s): Bao, Y., et al.
  • Journal Title: Genes to Cells 14 Pages: 1369-81
  • Peer Reviewed
• [Journal Article] Hippo pathway-dependent and-independent roles of RASSF6 (2009)
  • Author(s): Ikeda, M., et al.
  • Journal Title: Sci.Signal. 2
  • Peer Reviewed
• [Journal Article] Threonine 74 of MOB1 is a putative phosphorylation site by MST2 to form the scaffold to activate nuclear Dbf2-related kinase 1. (2008)
  • Author(s): Hirabayashi S, Nakagawa K, Sumita K, Hidaka S, Kawai T, Ikeda M, Kawata A, Ohno K, Hata Y.
  • Journal Title: Oncogene 27巻 Pages: 4281-4292
  • Peer Reviewed
• [Journal Article] Threonine 74 of MOB1 is a putative key phosphorylation site by MST2 to form the scaffold to activate nuclear Dbf2-related kinase 1. (2008)
  • Author(s): Hirabayashi, S., et.al.
  • Journal Title: Oncogene 27 Pages: 4281-92
  • Peer Reviewed
• [Presentation] アダプター分子MOB1のリン酸化がNuclear Dbf2-relatedキナーゼファミリーの選択的な活性化を制御する (2008)
  • Author(s): 中川健太郎、包義君、工藤琢己、壽美田一貴、畑裕
  • Organizer: 第31回日本分子生物学会年回、第81回日本生化学会大会
  • Place of Presentation: 神戸(ポスター発表 口頭発表)
• [Remarks] ホームページ等