中国医科大学《Oncogene》新文章

　　

生物通报道  来自中国医科大学的研究人员在新研究中利用甲状腺癌FRO细胞证实PKCδ介导BAG3 Ser187位点磷酸化诱导了的癌细胞的上皮间质转化，并促进了其侵袭力。相关论文发表在《Nature》杂志的子刊、国际著名肿瘤学刊物《Oncogene》上。

甲状腺癌（thyroidcarcinoma）是一种十分常见的内分泌腺恶性肿瘤，来源于甲状腺上皮细胞的恶性肿瘤。约占全身恶性肿瘤的1.3%～1.5%，且有增长趋势。2012年研究发现，女性甲状腺癌发病率已经跃升至女性易发肿瘤的第五位。

蛋白激酶C（PKC）是一类由多种同工酶组成的丝/苏氨酸蛋白激酶家族，是G蛋白偶联受体系统中的效应物，处于细胞内多条信号通路中心，是一系列细胞级联信号传导途径的关键环节，广泛参与正常细胞和异常细胞的增殖、分化、凋亡及细胞毒效应等多种生物学效应，在肿瘤的发生发展中起着重要作用。迄今为止，已发现至少13种PKC亚型，PKCδ是其中一种极其重要的亚型。

在当前的研究中，研究人员采用重组激活的PKCδ或显性失活的PKCδ转染中国仓鼠卵巢细胞，结合磷酸化蛋白富集、二维差异凝胶电泳技术（Two-dimensional difference gel electrophoresis）以及质谱法整体鉴别了PKCδ级联通路的候选因子。研究人员发现Bcl-2相关抗凋亡基因3(Bcl-2-associated athanogene 3, BAG3)是PKCδ级联通路的靶标，在体内BAG3与PKCδ发生了互作。此外，研究人员还证实BAG3以一种PKCδ依赖性方式在Ser187位点发生磷酸化。BAG3与多种细胞功能，包括细胞增殖、分化、凋亡、迁移、侵袭及巨自噬（macroautophagy）等有关。研究人员生成了野生型（WT）、Ser187Ala (S187A)-或Ser187Asp (S187D)-BAG3稳定表达的FRO细胞，证实BAG3磷酸化状态影响了FRO细胞的形态。最后，研究人员还首次证实了BAG3与上皮间质转化（EMT）程序有关，Ser187位点磷酸化状态对于BAG3的EMT调控起至关重要的作用。

新研究表明BAG3是PKCδ的一个新型底物，PKCδ介导的BAG3磷酸化与甲状腺癌细胞的EMT和侵袭密切相关。

（生物通：何嫱）

生物通推荐原文摘要：

PKCδ-mediated phosphorylation of BAG3 at Ser187 site induces epithelial−mesenchymal transition and enhances invasiveness in thyroid cancer FRO cells

AbstractProtein kinase C delta (PKCδ) is a serine (Ser)/threonine kinase, which regulates numerous cellular processes, including proliferation, differentiation, migration and apoptosis. In the current study, Chinese hamster ovary cells were transfected with either a constitutively activated PKCδ or a dominant negative PKCδ, phosphoprotein enrichment, two-dimensional difference gel electrophoresis and mass spectrometry was combined to globally identified candidates of PKCδ cascade. We found that Bcl-2 associated athanogene 3 (BAG3) was one of the targets of PKCδ cascade, and BAG3 interacted with PKCδ in vivo. In addition, we clarified that BAG3 was phosphorylate at Ser187 site in a PKCδ-dependent manner in vivo. BAG3 has been implicated in multiple cellular functions, including proliferation, differentiation, apoptosis, migration, invasion, macroautophagy and so on. We generated wild-type (WT)-, Ser187Ala (S187A)- or Ser187Asp (S187D)-BAG3 stably expressing FRO cells, and noticed that phosphorylation state of BAG3 influenced FRO morphology. Finally, for the first time, we showed that BAG3 was implicated in epithelial−mesenchymal transition (EMT) procedure, and phosphorylation state at Ser187 site had a critical role in EMT regulation by BAG3. Collectively, the current study indicates that BAG3 is a novel substrate of PKCδ, and PKCδ-mediated phosphorylation of BAG3 is implicated in EMT and invasiveness of thyroid cancer cells.