Stk40 links the pluripotency factor Oct4 to the Erk/MAPK pathway and controls extraembryonic endoderm differentiation
Stk40 links the pluripotency factor Oct4 to the Erk/MAPK pathway and controls extraembryonic endoderm differentiation
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Stk40 将多能因子 Oct4 连接到 Erk/MAPK 通路并控制胚外内胚层分化
DOI：
10.1073/pnas.0905657107
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发表时间：
2010-01-26
影响因子：
11.1
通讯作者：
Jin, Ying
中科院分区：
文献类型：
--
作者：
Li, Lingjie;Sun, Lei;Jin, Ying
胚胎干细胞（embryonic stem cells，ESCs）的自我更新和分化受细胞内转录因子和细胞外因子激活的信号通路的调控。转录因子Oct 4是维持ESC处于未分化状态的关键参与者，而已知Erk/MAPK通路对于ESC分化是重要的。然而，细胞内多能性因子调节ESCs中细胞外因子激活的信号通路的方式还不清楚。在这里，我们报告的目的基因Oct 4，丝氨酸/苏氨酸激酶40（Stk 40），这是能够激活Erk/MAPK通路，并诱导胚胎外内胚层（ExEn）在小鼠胚胎干细胞分化的鉴定。有趣的是，当注射到宿主胚泡中时，过表达Stk 40的细胞专门贡献于嵌合胚胎的ExEn层。相比之下，ESCs中Stk 40的缺失显著降低了ExEn的体外分化。在机制上，Stk 40与Rcn 2相互作用，Rcn 2也激活Erk 1/2以诱导小鼠ESC中的ExEn特化。此外，Rcn 2蛋白特异性地位于早期小鼠胚胎的ExEn层的细胞质中。重要的是，Rcn 2的敲低阻断Stk 40激活的Erk 1/2和ESC分化。因此，我们的研究建立了多能性因子Oct 4和Erk/MAPK信号通路之间的联系，并揭示了控制ExEn分化的Erk/MAPK激活中的协同信号。
Self-renewal and differentiation of embryonic stem cells (ESCs) are controlled by intracellular transcriptional factors and extracellular factor-activated signaling pathways. Transcription factor Oct4 is a key player maintaining ESCs in an undifferentiated state, whereas the Erk/MAPK pathway is known to be important for ESC differentiation. However, the manner in which intracellular pluripotency factors modulate extracellular factor-activated signaling pathways in ESCs is not well understood. Here, we report identification of a target gene of Oct4, serine/threonine kinase 40 (Stk40), which is able to activate the Erk/MAPK pathway and induce extraembryonic–endoderm (ExEn) differentiation in mouse ESCs. Interestingly, cells overexpressing Stk40 exclusively contribute to the ExEn layer of chimeric embryos when injected into host blastocysts. In contrast, deletion of Stk40 in ESCs markedly reduces ExEn differentiation in vitro. Mechanistically, Stk40 interacts with Rcn2, which also activates Erk1/2 to induce ExEn specification in mouse ESCs. Moreover, Rcn2 proteins are specifically located in the cytoplasm of the ExEn layer of early mouse embryos. Importantly, knockdown of Rcn2 blocks Stk40-activated Erk1/2 and ESC differentiation. Therefore, our study establishes a link between the pluripotency factor Oct4 and the Erk/MAPK signaling pathway, and it uncovers cooperating signals in the Erk/MAPK activation that control ExEn differentiation.