Wnt-5a/Ca2+-induced NFAT activity is counteracted by Wnt-5a/Yes-Cdc42-casein kinase 1α signaling in human mammary epithelial cells
Wnt-5a/Ca2+-induced NFAT activity is counteracted by Wnt-5a/Yes-Cdc42-casein kinase 1α signaling in human mammary epithelial cells
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DOI：
10.1128/mcb.02354-05
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发表时间：
2006-08-01
影响因子：
5.3
通讯作者：
Leandersson, Karin
中科院分区：
文献类型：
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作者：
Dejmek, Janna;Safholm, Annette;Leandersson, Karin
Wnt-5a已显示影响人乳腺癌细胞的转移行为，并且Wnt-5a表达的丧失与转移性疾病相关。我们在这里显示，NFAT 1，一个与乳腺癌转移相关的转录因子，在人乳腺上皮细胞中通过Ca 2+信号通路被Wnt-5a激活。这种激活同时被Wnt-5a诱导的Yes/Cdc 42信号通路抵消。Wnt-5a/Yes/Cdc 42信号的抑制延长了离子霉素诱导的NFAT 1激活的持续时间，这一观察结果揭示了该途径的普遍重要性。Wnt-5a诱导的NFAT 1抑制不需要糖原合成酶激酶3 β、JNK或Pak 1活性或细胞骨架的调节。相反，我们观察到Wnt-5a诱导NFAT 1/酪蛋白激酶1 α的复合物形成，即使在用离子霉素处理后也是如此，其在抑制Wnt-5a/Yes/Cdc 42信号传导途径后被阻断。我们的研究结果解释了为什么Wnt-5a/Ca 2+诱导的NFAT活性难以检测，并提出了一种新的机制，Wnt-5a可以抑制肿瘤特异性激动剂诱导的NFAT活性，从而抑制乳腺癌细胞的转移行为。
Wnt-5a has been shown to influence the metastatic behavior of human breast cancer cells, and the loss of Wnt-5a expression is associated with metastatic disease. We show here that NFAT1, a transcription factor connected with breast cancer metastasis, is activated by Wnt-5a through a Ca2+ signaling pathway in human breast epithelial cells. This activation was simultaneously counteracted by a Wnt-5a-induced Yes/Cdc42 signaling pathway. The observation that inhibition of the Wnt-5a/Yes/Cdc42 signal prolonged the duration of ionomycin-induced NFAT1 activation revealed the general importance of this pathway. The Wnt-5a-induced inhibition of NFAT1 did not require glycogen synthase kinase 3 beta, JNK, or Pak1 activity or modulation of the cytoskeleton. Instead, we observed that Wnt-5a induced a complex formation of NFAT1/casein kinase 1 alpha, even upon treatment with ionomycin, which was blocked upon inhibition of the Wnt-5a/Yes/Cdc42 signaling pathway. Our results explain why Wnt-5a/Ca2+-induced NFAT activity is hard to detect and suggest a novel mechanism by which Wnt-5a can suppress tumor-specific, agonist-induced NFAT activity and thus the metastatic behavior of breast cancer cells.