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Ensemble clustering of phosphoproteomic data identifies differences in protein interactions and cell-cell junction integrity of HER2-overexpressing cells.
Integrative Biology ( IF 2.5 ) Pub Date : 2017-05-12 , DOI: 10.1039/c7ib00054e
Katherine E Schaberg 1 , Venktesh S Shirure , Elizabeth A Worley , Steven C George , Kristen M Naegle
Affiliation  

Overexpression of HER2, a receptor tyrosine kinase of the ERBB family, in breast cancer is related to increased cancer progression and aggressiveness. A breast epithelial cell model with the single perturbation of HER2 overexpression is capable of replicating the increased aggressiveness of HER2 overexpressing cancers. In previous work, Wolf-Yadlin and colleagues (Wolf-Yadlin et al., Mol. Syst. Biol., 2006, 2) measured the proximal tyrosine phosphorylation dynamics of the parental and HER2 overexpressing cells (24H) in response to EGF. Here, we apply an ensemble clustering approach to dynamic phosphorylation measurements of the two cell models in order to identify signaling events that explain the increased migratory potential of HER2 overexpressing cells. The use of an ensemble approach for identifying relationships within a dataset and how these relationships change across datasets uncovers relationships that cannot be found by the direct comparison of dynamic responses in the two conditions. Of particular note is a drastic change in the clustering of SHC1 phosphorylation (on site Y349) from an EGFR-MAPK module in parental cells to a module consisting of an E-cadherin junction protein phosphorylation site, catenin delta-1 Y228, in HER2 overexpressing (24H) cells. Given the importance of E-cadherin junctions in healthy epithelial wound healing and migration, we chose to test the computationally-derived identification of altered cell junctions and CTNND1:SHC1 relationships. Our cell and molecular biology experiments demonstrate that SHC and CTNND1 interact in an EGF- and HER2-dependent manner and that the cell junctions are phenotypically affected by HER2, breaking down in response to EGF and yet avoiding apoptosis as a result of cell junction loss. The results suggest a mechanism by which HER2 alters the localization of the SHC-MAPK signaling axis and a phenotypic effect on cell junction integrity.

中文翻译:

磷酸化蛋白质组学数据的整体聚类可确定蛋白相互作用和HER2过表达细胞的细胞间连接完整性的差异。

HER2(ERBB家族的受体酪氨酸激酶)在乳腺癌中的过表达与癌症进展和侵略性增加有关。具有HER2过表达单次干扰的乳腺上皮细胞模型能够复制HER2过表达的癌症侵袭性增强。在以前的工作中,Wolf-Yadlin及其同事(Wolf-Yadlin等人,Mol。Syst。Biol。,2006,2)测量了亲本和HER2过表达细胞(24H)响应EGF的近端酪氨酸磷酸化动力学。在这里,我们将集成的聚类方法应用于两个细胞模型的动态磷酸化测量,以鉴定可解释HER2过表达细胞迁移潜力增加的信号传导事件。使用整体方法来识别数据集中的关系以及这些关系如何在数据集中变化时,会发现无法通过直接比较两种情况下的动态响应来找到的关系。特别值得注意的是,在HER2过表达中,SHC1磷酸化的聚簇(在Y349位点)从亲代细胞中的EGFR-MAPK模块到由E-钙粘蛋白结合蛋白磷酸化位点catenin delta-1 Y228组成的模块发生了急剧变化。 (24H)细胞。考虑到E-钙黏着蛋白连接在健康上皮伤口愈合和迁移中的重要性,我们选择测试计算得出的细胞连接改变和CTNND1:SHC1关系的鉴定。我们的细胞和分子生物学实验表明,SHC和CTNND1以EGF和HER2依赖性方式相互作用,并且细胞连接在表型上受HER2影响,响应EGF分解并避免由于细胞连接丢失而导致细胞凋亡。结果表明,HER2通过这种机制改变SHC-MAPK信号传导轴的定位以及对细胞连接完整性的表型效应。
更新日期:2019-11-01
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