Casein kinase 2 prevents mesenchymal transformation by maintaining Foxc2 in the cytoplasm.
Casein kinase 2 prevents mesenchymal transformation by maintaining Foxc2 in the cytoplasm.
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核Foxc 2是发育EMT过程中间充质转化的转录调节因子，并与恶性上皮的EMT相关。我们的实验室已经表明，在正常上皮细胞中，Foxc 2维持在细胞质中，在那里它促进上皮表型。Foxc 2的氨基末端有一个共识酪蛋白激酶2磷酸化位点在丝氨酸124，我们现在表明，CK 2协会与Foxc 2和磷酸化这个网站在体外。上皮细胞中CK 2 α/α′激酶亚基的敲低或抑制导致Foxc 2在细胞核中重新积聚。丝氨酸124突变为亮氨酸促进Foxc 2的组成性核定位和间充质基因的表达，而S124 D磷酸模拟物导致组成性细胞质定位和上皮维持。在恶性乳腺癌细胞中，CK 2 β调节亚基下调，FOXC 2存在于细胞核中，与α-SMA表达增加相关。这些细胞中CK 2 β表达的恢复导致Foxc 2的细胞质定位、α-SMA表达的降低以及细胞迁移和侵袭的减少。相反，在正常乳腺上皮细胞中，CK 2 β的敲低导致FOXC 2核定位，E-cadherin表达降低，α-SMA和波形蛋白表达增加，以及细胞迁移和侵袭增强。基于这些发现，我们认为Foxc 2通过CK 2 α/α′介导的丝氨酸124磷酸化在正常上皮细胞的细胞质中功能性维持，这依赖于通过CK 2 β调节亚基正确靶向全酶。
Nuclear Foxc2 is a transcriptional regulator of mesenchymal transformation during developmental EMT and has been associated with EMT in malignant epithelia. Our laboratory has shown that in normal epithelial cells Foxc2 is maintained in the cytoplasm where it promotes an epithelial phenotype. The Foxc2 amino terminus has a consensus casein kinase 2 phosphorylation site at serine 124, and we now show that CK2 associates with Foxc2 and phosphorylates this site in vitro. Knock-down or inhibition of the CK2α/α′ kinase subunit in epithelial cells causes de novo accumulation of Foxc2 in the nucleus. Mutation of serine 124 to leucine promotes constitutive nuclear localization of Foxc2 and expression of mesenchymal genes, whereas an S124D phosphomimetic leads to constitutive cytoplasmic localization and epithelial maintenance. In malignant breast cancer cells the CK2β regulatory subunit is downregulated and FOXC2 is found in the nucleus, correlating with an increase in α-SMA expression. Restoration of CK2β expression in these cells results in cytoplasmic localization of Foxc2, decreased α-SMA expression and reduced cell migration and invasion. In contrast, knockdown of CK2β in normal breast epithelial cells leads to FOXC2 nuclear localization, decreased E-cadherin expression, increased α-SMA and vimentin expression, and enhanced cell migration and invasion. Based on these findings we propose that Foxc2 is functionally maintained in the cytoplasm of normal epithelial cells by CK2α/α′-mediated phosphorylation at serine 124 that is dependent on proper targeting of the holoenzyme via the CK2β regulatory subunit.
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影响因子：
3.2
作者：
Pagano, Mario A.;Poletto, Giorgia;Pinna, Lorenzo A.
通讯作者：
Pinna, Lorenzo A.
DOI：
10.1083/jcb.130.2.393
发表时间：
1995-07
期刊：
The Journal of cell biology
影响因子：
--
作者：
Strutz F;Okada H;Lo CW;Danoff T;Carone RL;Tomaszewski JE;Neilson EG
通讯作者：
Neilson EG
影响因子：
2.5
作者：
Bard, Jonathan B. L.;Lam, Mei Sze;Aitken, Stuart
通讯作者：
Aitken, Stuart
影响因子：
4.8
作者：
Berry, FB;Saleem, RA;Walter, MA
通讯作者：
Walter, MA
DOI：
10.1073/pnas.0703900104
发表时间：
2007-06-12
影响因子：
11.1
作者：
Mani, Sendurai A.;Yang, Jing;Weinberg, Robert A.
通讯作者：
Weinberg, Robert A.