Inhibition of GSK-3beta promotes survival and proliferation of megakaryocytic cells through a beta-catenin-independent pathway.
Inhibition of GSK-3beta promotes survival and proliferation of megakaryocytic cells through a beta-catenin-independent pathway.
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GSK-3beta 的抑制通过不依赖 β-连环蛋白的途径促进巨核细胞的存活和增殖。
DOI：
10.1016/j.cellsig.2008.09.001
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发表时间：
2008
影响因子：
4.8
通讯作者：
Geddis,AmyE
中科院分区：
文献类型：
--
作者：
Soda,Mie;Willert,Karl;Kaushansky,Kenneth;Geddis,AmyE
血小板生成素 (TPO) 与其受体 c-Mpl 的相互作用启动对巨核细胞生成至关重要的细胞内信号。之前我们和其他人已经证明 TPO 激活 PI3K 和 Akt，并且该途径对于巨核细胞生长很重要。在这里，我们研究了 Akt 底物糖原合成酶激酶 (GSK)-3β 在 TPO 信号传导中的重要性。 GSK-3β 作为 PI3K 通路的一部分被 Akt 磷酸化和抑制。 GSK-3β 也可以通过独特的机制被 Wnt 信号传导抑制，从而导致转录因子 β-连环蛋白的磷酸化和积累减少。因此，我们想知道TPO和Wnt3a是否都可以抑制巨核细胞中的GSK-3β，以及它们是否可以协同作用以促进细胞生长。尽管 TPO 和 GSK-3β 的特定化学抑制剂都会导致巨核细胞系模型的存活和增殖增加，但无论是否存在 TPO，Wnt3a 处理都无法增加细胞生长，尽管诱导了高水平的 β-连环蛋白。类似地，无论存在或不存在 TPO，β-连环蛋白的组成型活性版本的表达都不会增加细胞生长，这表明 GSK-3β 抑制 TPO 信号下游的作用与 Wnt3a 诱导的作用不同，并且与 β-连环蛋白无关。 TPO 的生长促进作用不是由两个已知的 GSK-3β 靶标（细胞周期蛋白 D 或 HIF-1α）介导的。我们得出结论，GSK-3β 被 TPO 诱导的 Akt 磷酸化和抑制，通过不涉及 β-连环蛋白的途径促进巨核细胞的存活和增殖。
The interaction of thrombopoietin (TPO) with its receptor c-Mpl initiates intracellular signals that are critical for megakaryopoiesis. Previously we and others have shown that TPO activates PI3K and Akt and that this pathway is important for megakaryocyte growth. Here, we investigate the importance of the Akt substrate glycogen synthase kinase (GSK)-3β in TPO signaling. GSK-3β is phosphorylated and inhibited by Akt as part of the PI3K pathway. GSK-3β can also be inhibited by Wnt signaling through a distinct mechanism, leading to reduced phosphorylation and accumulation of the transcription factor β-catenin. Therefore, we asked if TPO and Wnt3a can both inhibit GSK-3β in megakaryocytic cells, and if they can act synergistically to promote cell growth. Although both TPO and specific chemical inhibitors of GSK-3β result in increased survival and proliferation in a megakaryocytic cell line model, treatment with Wnt3a failed to increase cell growth either in the absence or presence of TPO, despite inducing high levels of β-catenin. Similarly, expression of a constitutively active version of β-catenin did not increase cell growth either in the absence or presence of TPO, suggesting that the effects of GSK-3β inhibition downstream of TPO signaling are distinct from those induced by Wnt3a and independent of β-catenin. The growth promoting effects of TPO are not mediated by either of the two known GSK-3β targets, cyclin D or HIF-1α. We conclude that GSK-3β is phosphorylated and inhibited by TPO-induced Akt, promoting survival and proliferation in megakaryocytic cells through a pathway that does not involve β-catenin.