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Bridging the BMP and Wnt pathways by PI3 kinase/Akt and 14-3-3zeta.

机译：通过PI3激酶/ Akt和14-3-3zeta桥接BMP和Wnt途径。

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摘要

BMP, PTEN and Wnt/beta-catenin pathways are the three signaling pathways that control normal development and regeneration of the intestine, and contribute to intestinal polyposis when aberrant inactivation or activation occurs in each of these pathways. Using genetic targeting of BMPR1A in mice, we show that inactivation of BMP signaling results in multiple polyps due to an increased number of crypts and stem cells, accompanied by enhanced Wnt signaling in all proliferating intestine cells. However the increased transcriptional activity of Wnt effecter protein, beta-catenin, is found primarily in intestine stem cells (ISCs). Concurrently, PTEN, an inhibitor of PI3K/Akt pathway, is also primarily inactivated in the ISCs, leading to activation of Akt. Thus, Akt may contribute to activation of beta-catenin in ISCs in coordination with Wnt signaling. By conducting a proteomic analysis of the beta-catenin complex, we show that 14-3-3zeta exists in the beta-catenin complex and facilitates activation of beta-catenin by Akt, which, intriguingly, appears to be predominantly in ISCs. Thus, we propose that BMP signaling plays a role in inhibition of ISC self-renewal through suppression of Wnt/beta-catenin signaling in ISC, and this cross-talk is bridged, at least in part, through the PTEN/Akt pathway and further enforced by 14-3-3zeta.
机译：BMP，PTEN和Wnt /β-catenin途径是控制肠的正常发育和再生，并在每种途径中均出现异常失活或活化时，有助于肠道息肉病的三种信号途径。在小鼠中使用BMPR1A的基因靶向，我们显示BMP信号的失活会导致多发性息肉，这是由于隐窝和干细胞数量的增加，在所有增殖的肠细胞中伴随着Wnt信号的增强。但是，主要在肠干细胞（ISC）中发现Wnt效应蛋白β-catenin的转录活性增加。同时，PI3K / Akt途径的抑制剂PTEN也主要在ISC中失活，从而导致Akt活化。因此，Akt可能与Wnt信号传导协同作用促进ISC中β-catenin的活化。通过对β-catenin复合物进行蛋白质组学分析，我们显示14-3zeta存在于β-catenin复合物中，并促进了Akt对β-catenin的激活，这很有趣，这似乎主要发生在ISC中。因此，我们建议BMP信号传导通过抑制ISC中的Wnt /β-catenin信号传导在抑制ISC自我更新中起作用，并且这种串扰至少部分地通过PTEN / Akt途径桥接，并进一步由14-3-3zeta实施。

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