Pak1 kinase links ErbB2 to β-catenin in transformation of breast epithelial cells.
Pak1 kinase links ErbB2 to β-catenin in transformation of breast epithelial cells.
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DOI：
10.1158/0008-5472.can-12-4453
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发表时间：
2013-06-15
期刊：
影响因子：
11.2
通讯作者：
Chernoff J
中科院分区：
文献类型：
--
作者：
Arias-Romero LE;Villamar-Cruz O;Huang M;Hoeflich KP;Chernoff J
p21 激活激酶 1 (Pak1) 在人类乳腺癌中经常上调，并且是 ErbB2 转化乳腺上皮细胞所必需的。在这里，我们发现 Pak1 的缺失（而不是密切相关的 Pak2）会导致 β-catenin 及其靶基因的表达减少。在 MMTV-ErbB2 转基因小鼠中，Pak1 的缺失延长了存活时间，并且此类小鼠的乳腺组织显示出 β-catenin 的缺失。在 Ser 675（特定的 Pak1 磷酸化位点）处具有磷酸模拟突变的 β-连环蛋白突变体的表达，恢复了向 ErbB2 阳性、Pak1 缺陷的乳腺上皮细胞的转化。当用 Pak 或 β-catenin 小分子抑制剂治疗时，携带 ErbB2 阳性乳腺癌细胞异种移植物的小鼠显示出肿瘤消退，并且两种药物的联合抑制具有协同作用。这些数据描绘了乳腺上皮细胞有效转化所需的从 ErbB2 到 Pak 到 β-连环蛋白的信号传导途径，并提出了 ErbB2 阳性乳腺癌的新治疗策略。
p21-activated kinase-1 (Pak1) is frequently upregulated in human breast cancer and is required for transformation of mammary epithelial cells by ErbB2. Here we show that loss of Pak1, but not the closely related Pak2, leads to diminished expression of β-catenin and its target genes. In MMTV-ErbB2 transgenic mice, loss of Pak1 prolonged survival, and mammary tissues of such mice showed loss of β-catenin. Expression of a β-catenin mutant bearing a phospho-mimetic mutation at Ser 675, a specific Pak1 phosphorylation site, restored transformation to ErbB2-positive, Pak1-deficient mammary epithelial cells. Mice bearing xenografts of ErbB2-positive breast cancer cells showed tumor regression when treated with small molecule inhibitors of Pak or β-catenin, and combined inhibition by both agents was synergistic. These data delineate a signaling pathway from ErbB2 to Pak to β-catenin that is required for efficient transformation of mammary epithelial cells, and suggest new therapeutic strategies in ErbB2-positive breast cancer.