c-Yes tyrosine kinase is a potent suppressor of ES cell differentiation and antagonizes the actions of its closest phylogenetic relative, c-Src.
c-Yes tyrosine kinase is a potent suppressor of ES cell differentiation and antagonizes the actions of its closest phylogenetic relative, c-Src.
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DOI：
10.1021/cb400249b
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发表时间：
2014-01-17
影响因子：
4
通讯作者：
Smithgall, Thomas E.
中科院分区：
文献类型：
--
作者：
Zhang, Xiong;Meyn, Malcolm A., III;Smithgall, Thomas E.
ES细胞来源于囊胚期胚胎的内细胞团，具有自我更新和多能性的特点。先前的研究表明，Src 家族酪氨酸激酶在 ES 细胞分化过程中表现出动态表达和活性变化，表明在控制发育命运方面具有不同的功能。在这里，我们使用 ES 细胞来检验这样的假设：c-Src 及其最接近的系统发育亲戚 c-Yes，尽管它们具有很强的同源性，但在生物学上却相反。与c-Src不同，活性c-Yes的强制表达通过维持多能性基因表达来阻止ES细胞分化为胚状体。为了探索 c-Src 和 c-Yes 在 ES 细胞分化中的相互作用，我们设计了对 A-419259（Src 激酶家族的有效吡咯并嘧啶抑制剂）具有抗性的 c-Src 和 c-Yes 突变体。先前的研究表明，A-419259 治疗可阻断 ES 细胞中的所有 Src 家族激酶活性，从而防止分化，同时保持多能性。抑制剂抗性的 c-Src 而非 c-Yes 的表达挽救了 A-419259 的分化阻断，从而产生了具有原始外胚层和内胚层特性的细胞群。值得注意的是，当抑制剂抗性的 c-Src 和 c-Yes 在 ES 细胞中一起表达时，c-Yes 活性抑制 c-Src 介导的分化。这些研究表明，即使是密切相关的激酶，例如 c-Src 和 c-Yes，在同一细胞类型中也具有独特且相反的功能。 c-Src 与 c-Yes 活性的选择性激动剂或抑制剂可能允许对 ES 细胞命运进行更精确的药理学操纵，并在表达多个 Src 家族成员（例如肿瘤细胞）的其他生物系统中具有更广泛的应用。
ES cells are derived from the inner cell mass of the blastocyst stage embryo and are characterized by self-renewal and pluripotency. Previous work has shown that Src-family tyrosine kinases display dynamic expression and activity changes during ES cell differentiation, suggesting distinct functions in the control of developmental fate. Here we used ES cells to test the hypothesis that c-Src and its closest phylogenetic relative, c-Yes, act in biological opposition despite their strong homology. Unlike c-Src, enforced expression of active c-Yes blocked ES cell differentiation to embryoid bodies by maintaining pluripotency gene expression. To explore the interplay of c-Src and c-Yes in ES cell differentiation, we engineered c-Src and c-Yes mutants that are resistant to A-419259, a potent pyrrolopyrimidine inhibitor of the Src kinase family. Previous studies have shown that A-419259 treatment blocks all Src-family kinase activity in ES cells, preventing differentiation while maintaining pluripotency. Expression of inhibitor-resistant c-Src but not c-Yes rescued the A-419259 differentiation block, resulting in a cell population with properties of both primitive ectoderm and endoderm. Remarkably, when inhibitor-resistant c-Src and c-Yes were expressed together in ES cells, c-Yes activity suppressed c-Src mediated differentiation. These studies show that even closely related kinases such as c-Src and c-Yes have unique and opposing functions in the same cell type. Selective agonists or inhibitors of c-Src vs. c-Yes activity may allow more precise pharmacological manipulation of ES cell fate and have broader applications in other biological systems which express multiple Src family members such as tumor cells.
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影响因子：
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作者：
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通讯作者：
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