Rho GTPase activity modulates Wnt3a/beta-catenin signaling.
Rho GTPase activity modulates Wnt3a/beta-catenin signaling.
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DOI：
10.1016/j.cellsig.2009.05.010
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发表时间：
2009-11
影响因子：
4.8
通讯作者：
Fields TA
中科院分区：
文献类型：
--
作者：
Rossol-Allison J;Stemmle LN;Swenson-Fields KI;Kelly P;Fields PE;McCall SJ;Casey PJ;Fields TA
WNT蛋白构成一个分泌的信号分子家族，调节对发育至关重要的高度保守的途径，当异常激活时，在一些人类癌症中驱动肿瘤发生。研究最广泛的Wnt信号级联的一个关键特征是胞内β-连环蛋白的稳定，导致β-连环蛋白的核转位和多个靶基因的转录激活。除了这种典型的β依赖的连环蛋白途径外，WNT3a还被证明可以刺激RhoA GTP酶。虽然激活的Rho对非典范的Wnt信号的重要性已经被很好地认识到，但WNT3a刺激的RhoA对典范的β-连环蛋白依赖的转录的潜在贡献还没有被检验，这是本研究的重点。我们发现，激活的Rho是WNT3a刺激C3H10T1/2间充质干细胞向成骨细胞分化所必需的，这是一种由稳定的β-连环蛋白介导的生物学现象。利用表达芯片和实时RTPCR分析，我们发现WNT3a刺激的靶基因亚集的转录是Rho依赖的，这表明这些Wnt靶标的完全诱导需要β-catenin和Rho的激活。值得注意的是，β-连环蛋白的稳定和WNT3a刺激的核转位都不受RhoA抑制或激活的影响。这些发现确定Rho激活是典型的WNT3a刺激的、β依赖的连环蛋白转录程序的关键元件。
Wnt proteins constitute a family of secreted signaling molecules that regulate highly conserved pathways essential for development and, when aberrantly activated, drive oncogenesis in a number of human cancers. A key feature of the most widely studied Wnt signaling cascade is the stabilization of cytosolic β-catenin, resulting in β-catenin nuclear translocation and transcriptional activation of multiple target genes. In addition to this canonical, β-catenin-dependent pathway, Wnt3A has also been shown to stimulate RhoA GTPase. While the importance of activated Rho to non-canonical Wnt signaling is well appreciated, the potential contribution of Wnt3A–stimulated RhoA to canonical β-catenin-dependent transcription has not been examined and is the focus of this study. We find that activated Rho is required for Wnt3A–stimulated osteoblastic differentiation in C3H10T1/2 mesenchymal stem cells, a biological phenomenon mediated by stabilized β–catenin. Using expression microarrays and real-time RT-PCR analysis, we show that Wnt3A–stimulated transcription of a subset of target genes is Rho-dependent, indicating that full induction of these Wnt targets requires both β-catenin and Rho activation. Significantly, neither β–catenin stabilization nor nuclear translocation stimulated by Wnt3A is affected by inhibition or activation of RhoA. These findings identify Rho activation as a critical element of the canonical Wnt3A–stimulated, β–catenin-dependent transcriptional program.
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影响因子：
10.5
作者：
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通讯作者：
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影响因子：
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作者：
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DOI：
10.1016/j.bbrc.2005.03.007
发表时间：
2005-05-06
影响因子：
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作者：
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