Role of lung cancer cells to fibrosis and regulation of TGF-beta signaling by EGF

• Project/Area Number: 20790580
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Respiratory organ internal medicine
• Research Institution: Japanese Foundation For Cancer Research
• Principal Investigator: KOINUMA Daizo Japanese Foundation For Cancer Research, 大学院・医学系研究科, 講師 (80375071)
• Project Period (FY): 2008 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2009: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2008: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 癌 / シグナル伝達 / 細胞・組織 / 発生・分化 / 発現制御 / 発生・文化

Research Abstract

We identified Pin1, a peptidylprolyl cis-trans isomerase, as a novel protein binding Smads. Pin1 interacted with Smad2 and Smad3. This interaction was enhanced by the phosphorylation of (S/T)P motifs in the Smad linker region by EGF or mutant of its downstream protein RAS. (S/T)P motif phosphorylation also enhanced the interaction of Smad2/3 with Smurf2. Pin1 reduced Smad2/3 protein levels in a manner dependent on its peptidyl-prolyl cis-trans isomerase activity. Knockdown of Pin1 increased the protein levels of endogenous Smad2/3. In addition, Pin1 both enhanced the interaction of Smurf2 with Smads and enhanced Smad ubiquitination. Pin1 inhibited TGF-beta-induced transcription and gene expression, including connective tissue growth factor, suggesting that Pin1 negatively regulates TGF-beta signaling by down-regulating Smad2/3 protein levels via induction of Smurf2-mediated ubiquitin-proteasomal degradation.

Research Products

• [Journal Article] Pin1 down-regulates transforming growth factor-beta (TGF-beta) signaling by inducing degradation of Smad proteins. (2009)
  • Author(s): Nakano A, Koinuma D, Miyazawa K, Uchida T, Saitoh M, Kawabata M, Hanai J, Akiyama H, Abe M, Miyazono K, Matsumoto T, Imamura T
  • Journal Title: J Biol Chem. 284 Pages: 6109-6115
  • Peer Reviewed
• [Journal Article] Pin1 down-regulates transforming growth factor-beta(TGF-deta) signaling by inducing degradation of Smad proteins. (2009)
  • Author(s): Ayako Nakano
  • Journal Title: Journal of Biological Chemistry 284 Pages: 6109-6115
  • Peer Reviewed