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TGF-Beta Induced Erk Phosphorylation of Smad LinkerudRegion Regulates Smad Signaling

机译:TGF-β诱导smad连接子的Erk磷酸化区域调节smad信令

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摘要

The Transforming Growth Factor-Beta (TGF-β) family is involved in regulating a variety of cellular processes such as apoptosis, differentiation, and proliferation. TGF-β binding to a Serine/Threonine kinase receptor complex causes the recruitment and subsequent activation of transcription factors known as smad2 and smad3. These proteins subsequently translocate into the nucleus to negatively or positively regulate gene expression. In this study, we define a second signaling pathway leading to TGF-β receptor activation of Extracellular Signal Regulated Kinase (Erk) in a cell-type dependent manner. TGF-β induced Erk activation was found in phenotypically normal mesenchymal cells, but not normal epithelial cells. By activating phosphotidylinositol 3-kinase (PI3K), TGF-β stimulates p21-activated kinase2 (Pak2) to phosphorylate c-Raf, ultimately resulting in Erk activation. Activation of Erk was necessary for TGF-β induced fibroblast replication. In addition, Erk phosphorylated the linker region of nuclear localized smads, resulting in increased half-life of C-terminal phospho-smad 2 and 3 and increased duration of smad target gene transcription. Together, these data show that in mesenchymal cell types the TGF-β/PI3K/Pak2/Raf/MEK/Erk pathway regulates smad signaling, is critical for TGF-β-induced growth and is part of an integrated signaling web containing multiple interacting pathways rather than discrete smad/non-smad pathways.
机译:转化生长因子-β(TGF-β)家族参与调节各种细胞过程,例如凋亡,分化和增殖。与丝氨酸/苏氨酸激酶受体复合物结合的TGF-β导致募集并随后激活称为smad2和smad3的转录因子。这些蛋白质随后易位到细胞核中,以负向或正向调节基因表达。在这项研究中,我们定义了第二种信号通路,以细胞类型依赖性方式导致TGF-β受体激活细胞外信号调节激酶(Erk)。在表型上正常的间充质细胞中发现了TGF-β诱导的Erk激活,但在正常的上皮细胞中没有发现。通过激活磷酸肌醇3激酶(PI3K),TGF-β刺激p21激活的激酶2(Pak2)磷酸化c-Raf,最终导致Erk激活。 Erk的激活对于TGF-β诱导的成纤维细胞复制是必需的。另外,Erk磷酸化核定位的smads的接头区域,导致C末端磷酸smad 2和3的半衰期延长,并且smad靶基因转录的持续时间延长。总之,这些数据表明,在间充质细胞类型中,TGF-β/ PI3K / Pak2 / Raf / MEK / Erk途径调节smad信号传导,对TGF-β诱导的生长至关重要,并且是包含多个相互作用途径的整合信号网的一部分而不是离散的smad / non-smad通路。

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