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

我们鉴定PIN1是一种新的结合蛋白的Smads，它是一种多肽基-脯氨酰顺反异构酶。Pin1与Smad2和Smad3相互作用。这种相互作用通过表皮生长因子或其下游蛋白RAS的突变体使Smad连接区的(S/T)P基序磷酸化而增强。(S/T)P基序的磷酸化也增强了Smad2/3与SMurf2的相互作用。Pin1降低Smad2/3蛋白水平的作用依赖于其肽基-脯氨基顺式-反式异构酶活性。Pin1基因的敲除增加了内源性Smad2/3的蛋白水平。此外，Pin1既增强了SMurf2与Smads的相互作用，又增强了Smad的泛素化。Pin1抑制TGF-β诱导的转录和基因表达，包括结缔组织生长因子，提示Pin1通过诱导SMurf2介导的泛素蛋白酶体降解而下调Smad2/3蛋白水平，从而负向调节TGF-β信号转导。

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.