Myocardin-related transcription factor A (MRTF-A) activity-dependent cell adhesion is correlated to focal adhesion kinase (FAK) activity.
Myocardin-related transcription factor A (MRTF-A) activity-dependent cell adhesion is correlated to focal adhesion kinase (FAK) activity.
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DOI：
10.18632/oncotarget.12350
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发表时间：
2016-11-01
期刊：
影响因子：
--
通讯作者：
Sobue K
中科院分区：
文献类型：
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作者：
Kishi T;Mayanagi T;Iwabuchi S;Akasaka T;Sobue K
细胞-基质粘附的调节与肿瘤细胞的恶性表型密切相关，并在其迁移、侵袭和转移中起作用。粘着斑（Focal adhesions，FA）是一种动态的粘附结构，它将细胞锚在细胞外基质上。肌心肽相关转录因子（MRTF），血清反应因子（SRF）的共调节因子，调节一组编码肌动蛋白细胞骨架/FA相关蛋白的基因的表达。在这里，我们证明了在B16 F10黑色素瘤细胞中强制表达组成型活性MRTF-A（CA-MRTF-A）诱导肌动蛋白细胞骨架和FA蛋白的上调，导致FA重组和细胞迁移的抑制。CA-MRTF-A的表达显著增加了粘着斑激酶（FAK）和桩蛋白的磷酸化，这是FA动力学的重要组成部分。值得注意的是，FAK激活是由上调的整合素的聚集触发的。我们的研究结果表明，MRTF-SRF依赖的调节细胞迁移需要的肌动蛋白细胞骨架/FA蛋白的上调和整合素介导的调节FA组件通过FAK/Src途径。我们还证明了MRTF依赖性转录的激活与各种肿瘤细胞中的FAK激活相关。阐明MRTF和FAK活性之间的相关性将是肿瘤细胞迁移焦点的有效治疗靶点。
The regulation of cell-substrate adhesion is tightly linked to the malignant phenotype of tumor cells and plays a role in their migration, invasion, and metastasis. Focal adhesions (FAs) are dynamic adhesion structures that anchor the cell to the extracellular matrix. Myocardin-related transcription factors (MRTFs), co-regulators of the serum response factor (SRF), regulate expression of a set of genes encoding actin cytoskeletal/FA-related proteins. Here we demonstrated that the forced expression of a constitutively active MRTF-A (CA-MRTF-A) in B16F10 melanoma cells induced the up-regulation of actin cytoskeletal and FA proteins, resulting in FA reorganization and the suppression of cell migration. Expression of CA-MRTF-A markedly increased phosphorylation of focal adhesion kinase (FAK) and paxillin, which are important components for FA dynamics. Notably, FAK activation was triggered by the clustering of up-regulated integrins. Our results revealed that the MRTF-SRF-dependent regulation of cell migration requires both the up-regulation of actin cytoskeletal/FA proteins and the integrin-mediated regulation of FA components via the FAK/Src pathway. We also demonstrated that activation of the MRTF-dependent transcription correlates FAK activation in various tumor cells. The elucidation of the correlation between MRTF and FAK activities would be an effective therapeutic target in focus of tumor cell migration.