Abstract
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.
Highlights
Cell motility accompanied with its adhesive property is crucially involved in tumor malignancy [1]
Our present study showed that CA-Myocardin-related transcription factors (MRTFs)-A-transfected B16F10 melanoma and a group of tumor cells exhibited prominent actin cytoskeletal and Focal adhesions (FAs) reorganization
In contrast to previous studies, which merely focused on the correlation between the MTRF-mediated up-regulation of actin cytoskeletal/FA proteins and alterations in cell morphology and migration, the present study revealed that MRTF-mediated cellular changes critically require the integrin-mediated regulation of FA components via activation of the focal adhesion kinase (FAK)/Src-paxillin pathway (Figure 10)
Summary
Cell motility accompanied with its adhesive property is crucially involved in tumor malignancy [1]. Recent studies reports that MRTFs are involved in invasive and metastatic activities via regulating actin cytoskeletal gene expression [5, 6, 7]. Previous reports indicate that during epithelial-mesenchymal transition (EMT), epithelial cells or carcinoma cells intensely express a number of actin www.impactjournals.com/oncotarget cytoskeletal/FA proteins and acquire a highly motile, invasive, and metastatic phenotype [13, 14]. These studies indicate that the MRTF-SRF transcription pathway regulates tumor cell motility by modulating the expression of cytoskeletal/FA proteins, the molecular mechanisms have remained unclear
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