Research Abstract

PI 3キナーゼ依存性のPlk1-Ser99リン酸化は14-3-3γの結合を促進し、分裂中期から後期への移行に必要である

PI 3-kinase-dependent phosphorylation of Plk1–Ser99 promotes association with 14-3-3γ and is required for metaphase–anaphase transition

2013年5月21日 Nature Communications 4 : 1882 doi: 10.1038/ncomms2879


笠原 広介1,2, 後藤 英仁1,3, 井澤 一郎1, 清野 透4, 渡邊 信元5, Sabine Elowe6,7, Erich A Nigg8 & 稲垣 昌樹1,3

  1. 愛知県がんセンター研究所 発がん制御研究部
  2. 名古屋市立大学大学院 薬学研究科 腫瘍制御学
  3. 名古屋大学大学院 医学系研究科 細胞腫瘍学
  4. 国立がん研究センター ウイルス発がん研究分野
  5. 独立行政法人 理化学研究所 基幹研究所 化合物ライブラリ評価研究チーム
  6. The CHUQ Research Center(カナダ)
  7. ラヴァル大学(カナダ)
  8. バーゼル大学(スイス)
Polo-like kinase 1 (Plk1) controls multiple aspects of mitosis and is activated through its phosphorylation at Thr210. Here we identify Ser99 on Plk1 as a novel mitosis-specific phosphorylation site, which operates independently of Plk1–Thr210 phosphorylation. Plk1–Ser99 phosphorylation creates a docking site for 14-3-3γ, and this interaction stimulates the catalytic activity of Plk1. Knockdown of 14-3-3γ or replacement of wild-type (WT) Plk1 by a Ser99-phospho-blocking mutant leads to a prometaphase/metaphase-like arrest due to the activation of the spindle assembly checkpoint. Inhibition of phosphatidylinositol 3-kinase (PI3K) and Akt significantly reduces the level of Plk1–Ser99 phosphorylation and delays metaphase to anaphase transition. Plk1–Ser99 phosphorylation requires not only Akt activity but also protein(s) associated with Plk1 in a mitosis-specific manner. Therefore, mitotic Plk1 activity is regulated not only by Plk1–Thr210 phosphorylation, but also by Plk1 binding to 14-3-3γ following Plk1–Ser99 phosphorylation downstream of the PI3K–Akt signalling pathway. This novel Plk1 activation pathway controls proper progression from metaphase to anaphase.