Intracellular signaling cascades triggered by the NK1 fragment of hepatocyte growth factor in human prostate epithelial cell line PNT1A.
Intracellular signaling cascades triggered by the NK1 fragment of hepatocyte growth factor in human prostate epithelial cell line PNT1A.
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DOI：
10.1016/j.cellsig.2011.07.005
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发表时间：
2011-12
影响因子：
4.8
通讯作者：
L. Pavone;F. Cattaneo;S. Rea;V. De Pasquale;A. Spina;Elena Sauchelli;V. Mastellone;R. Ammendola
中科院分区：
文献类型：
--
作者：
L. Pavone;F. Cattaneo;S. Rea;V. De Pasquale;A. Spina;Elena Sauchelli;V. Mastellone;R. Ammendola
肝细胞生长因子(HGF)/c-met信号转导系统在促进多种细胞的增殖、存活、迁移、创伤修复和分支等方面发挥着重要作用。在正常前列腺组织中，HGF作为间质-上皮细胞相互作用的介质发挥着重要作用，但HGF/c-Met相互作用在正常前列腺和前列腺癌中的确切生物学功能尚不清楚。HGF有两个自然产生的剪接变体，其中最小的NK1由HGF氨基末端通过第一个kringle结构域组成。我们研究了NK1对人前列腺上皮细胞系PNT1A的细胞内信号转导和细胞形态的影响，该细胞具有与正常前列腺上皮相似的分子和生化特性。我们证明了这些细胞表达功能性的c-met，并且细胞暴露于NK1诱导c-met的1313/1349/1356残基的酪氨酸的磷酸化，为信号分子提供对接位置。我们观察到ERK1/2、Akt、c-Src、p125FAK、Smad2/3和STAT3的磷酸化水平增加，上皮细胞-细胞黏附标记E-钙粘附素的表达下调，间充质标记Vimentin、纤维连接蛋白、纽蛋白、α-肌动蛋白和α-平滑肌肌动蛋白的表达水平增强。这会导致细胞增殖，出现间充质表型，出现类似细胞散布的形态变化，并促进伤口愈合。我们的发现突出了NK1在非致癌的人类前列腺上皮细胞中的功能，并提供了一幅由NK1在一种独特的细胞系中触发的信号通路的图片。
Hepatocyte Growth Factor (HGF)/c-MET signaling has an emerging role in promoting cell proliferation, survival, migration, wound repair and branching in a variety of cell types. HGF plays a crucial role as a mediator of stromal–epithelial interactions in the normal prostate but the precise biological function of HGF/c-Met interaction in the normal prostate and in prostate cancer is not clear. HGF has two naturally occurring splice variants and NK1, the smallest of these HGF variants, consists of the HGF amino terminus through the first kringle domain. We evaluated the intracellular signaling cascades and the morphological changes triggered by NK1 in human prostate epithelial cell line PNT1A which shows molecular and biochemical properties close to the normal prostate epithelium. We demonstrated that these cells express a functional c-MET, and cell exposure to NK1 induces the phosphorylation of tyrosines 1313/1349/1356 residues of c-MET which provide docking sites for signaling molecules. We observed an increased phosphorylation of ERK1/2, Akt, c-Src, p125FAK, SMAD2/3, and STAT3, down-regulation of the expression of epithelial cell–cell adhesion marker E-cadherin, and enhanced expression levels of mesenchymal markers vimentin, fibronectin, vinculin, α-actinin, and α-smooth muscle actin. This results in cell proliferation, in the appearance of a mesenchymal phenotype, in morphological changes resembling cell scattering and in wound healing. Our findings highlight the function of NK1 in non-tumorigenic human prostatic epithelial cells and provide a picture of the signaling pathways triggered by NK1 in a unique cell line.