2009 Fiscal Year Final Research Report

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

Research Project

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
Keywords	癌 / シグナル伝達 / 細胞・組織 / 発生・分化 / 発現制御
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.