ERK1 and ERK2 regulate embryonic stem cell self-renewal through phosphorylation of Klf4
ERK1 and ERK2 regulate embryonic stem cell self-renewal through phosphorylation of Klf4
复制标题
DOI：
10.1038/nsmb.2217
复制
发表时间：
2012-03-01
影响因子：
16.8
通讯作者：
Dong, Zigang
中科院分区：
文献类型：
--
作者：
Kim, Myoung Ok;Kim, Sung-Hyun;Dong, Zigang
理解和控制干细胞平衡自我更新与分化的机制对于干细胞治疗非常重要。Klf 4促进胚胎干细胞的自我更新，但调节Klf 4这种作用的确切机制尚不清楚。我们发现ERK 1或ERK 2结合Klf 4的活化结构域并直接磷酸化Klf 4的Ser 123。这种磷酸化抑制Klf 4活性，诱导胚胎干细胞分化。相反，Klf 4磷酸化的抑制增强Klf 4活性并抑制胚胎干细胞分化。值得注意的是，ERK对Klf 4的磷酸化导致F盒蛋白β TrCP 1或β TrCP 2（泛素E3连接酶的组分）募集并结合到Klf 4 N-末端结构域，这导致Klf 4泛素化和降解。总之，我们的数据提供了ERK 1和ERK 2在调节Klf 4介导的小鼠胚胎干细胞自我更新中的作用的分子基础。
Understanding and controlling the mechanism by which stem cells balance self-renewal versus differentiation is of great importance for stem cell therapeutics. Klf4 promotes the self-renewal of embryonic stem cells, but the precise mechanism regulating this role of Klf4 is unclear. We found that ERK1 or ERK2 binds the activation domain of Klf4 and directly phosphorylates Klf4 at Ser123. This phosphorylation suppresses Klf4 activity, inducing embryonic stem cell differentiation. Conversely, inhibition of Klf4 phosphorylation enhances Klf4 activity and suppresses embryonic stem cell differentiation. Notably, phosphorylation of Klf4 by ERKs causes recruitment and binding of the F-box proteins beta TrCP1 or beta TrCP2 ( components of an ubiquitin E3 ligase) to the Klf4 N-terminal domain, which results in Klf4 ubiquitination and degradation. Overall, our data provide a molecular basis for the role of ERK1 and ERK2 in regulating Klf4-mediated mouse embryonic stem cell self-renewal.