S100A4, a Mediator of Metastasis

Garrett, Sarah; Varney, Kristen M.; Weber, David J.; Bresnick, Anne R.

doi:10.1074/jbc.r500017200

Cited by 315 publications

(319 citation statements)

References 81 publications

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“…Therefore, S100A4 can promote metastasis and crossing mice that overexpress S100A4 in the mammary epithelium with mouse models of metastasis dramatically increases the incidence of metastasis (Davies et al, 1996). Finally, S100A4 expression is associated with a metastatic phenotype in multiple types of carcinoma, including breast cancer (Garrett et al, 2006). Similarly, elevated levels of LCN2 expression have been reported in various cancers, including breast cancer.…”

Section: Discussionmentioning

confidence: 85%

“…Indeed, it has been shown that, in breast cancer, intracellular S100A4 can induce cell motility in part through its ability to interact with myosin-IIA and extracellular S100A4 can stimulate MMP-13 activity, possibly contributing to tumor invasion (Garrett et al, 2006;Li and Bresnick, 2006). Therefore, S100A4 can promote metastasis and crossing mice that overexpress S100A4 in the mammary epithelium with mouse models of metastasis dramatically increases the incidence of metastasis (Davies et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

“…S100A4 or metastasin, which is a member of the S100 family of calcium-binding proteins, has been shown to have an important role in breast cancer progression (Helfman et al, 2005;Garrett Regulation of NFAT5 by ddx5/ddx17 S Germann et al et al, 2006). We have recently reported that lipocalin 2 (LCN2), which also plays a role in breast cancer progression (Yang et al, 2009;Leng et al, 2011), is regulated by NFAT transcriptional factors (Fougere et al, 2010).…”

Section: Nfat5 Ddx17mentioning

confidence: 99%

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Dual role of the ddx5/ddx17 RNA helicases in the control of the pro-migratory NFAT5 transcription factor

et al. 2012

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Ddx5 and ddx17 are two highly related RNA helicases involved in both transcription and splicing. These proteins coactivate transcription factors involved in cancer such as the estrogen receptor alpha, p53 and beta-catenin. Ddx5 and ddx17 are part of the splicing machinery and can modulate alternative splicing, the main mechanism increasing the proteome diversity. Alternative splicing also has a role in gene expression level regulation when it is coupled to the nonsensemediated mRNA decay (NMD) pathway. In this work, we report that ddx5 and ddx17 have a dual role in the control of the pro-migratory NFAT5 transcription factor. First, ddx5 and ddx17 act as transcriptional coactivators of NFAT5 and are required for activating NFAT5 target genes involved in tumor cell migration. Second, at the splicing level, ddx5 and ddx17 increase the inclusion of NFAT5 exon 5. As exon 5 contains a pre-mature translation termination codon, its inclusion leads to the regulation of NFAT5 mRNAs by the NMD pathway and to a decrease in NFAT5 protein level. Therefore, we demonstrated for the first time that a transcriptional coregulator can simultaneously regulate the transcriptional activity and alternative splicing of a transcription factor. This dual regulation, where ddx5 and ddx17 enhance the transcriptional activity of NFAT5 although reducing its protein expression level, suggests a critical role for ddx5 and ddx17 in tumor cell migration through the fine regulation of NFAT5 pathway.

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Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Nfat5 Ddx17mentioning

confidence: 99%

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Dual role of the ddx5/ddx17 RNA helicases in the control of the pro-migratory NFAT5 transcription factor

et al. 2012

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“…S100A4 is reported to play a key role in development of advanced cancer stages including investigations in tumour xenograft and genetically engineered mouse models 3, 31, 32. However, the activity of extracellular S100A4 within the metastatic cascade, and the participation of S100A4 in malignant melanoma are still not fully understood.…”

Section: Discussionmentioning

confidence: 99%

Interaction of extracellular S100A4 with RAGE prompts prometastatic activation of A375 melanoma cells

Herwig

Belter

Wolf

et al. 2016

J Cellular Molecular Medi

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S100A4, a member of the S100 protein family of EF‐hand calcium‐binding proteins, is overexpressed in various tumour entities, including melanoma, and plays an important role in tumour progression. Several studies in epithelial and mesenchymal tumours revealed a correlation between extracellular S100A4 and metastasis. However, exact mechanisms how S100A4 stimulates metastasis in melanoma are still unknown. From a pilot experiment on baseline synthesis and secretion of S100A4 in human melanoma cell lines, which are in broad laboratory use, A375 wild‐type cells and, additionally, newly generated A375 cell lines stably transfected with human S100A4 (A375‐hS100A4) or human receptor for advanced glycation endproducts (A375‐hRAGE), were selected to investigate the influence of extracellular S100A4 on cell motility, adhesion, migration and invasion in more detail. We demonstrated that A375 cells actively secrete S100A4 in the extracellular space via an endoplasmic reticulum‐Golgi‐dependent pathway. S100A4 overexpression and secretion resulted in prometastatic activation of A375 cells. Moreover, we determined the influence of S100A4‐RAGE interaction and its blockade on A375, A375‐hS100A4, A375‐hRAGE cells, and showed that interaction of RAGE with extracellular S100A4 contributes to the observed activation of A375 cells. This investigation reveals additional molecular targets for therapeutic approaches aiming at blockade of ligand binding to RAGE or RAGE signalling to inhibit melanoma metastasis.

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“…S100A4 binding is itself blocked by casein-kinase II-dependent phosphorylation of M2A HC on Ser1943, thereby preventing S100A4 inhibition of filament assembly (Dulyaninova et al 2005). Because S100A4 protein is a marker associated with human cancer, its binding to M2A is seen to be critical to onset of metastasis (Garrett et al 2006).…”

Section: The Players: Binding Partners and Regulationmentioning

confidence: 99%

Conventional myosins – unconventional functions

et al. 2010

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While the discovery of unconventional myosins raised expectations that their actions were responsible for most aspects of actin-based cell motility, few anticipated the wide range of cellular functions that would remain the purview of conventional two-headed myosins. The three nonsarcomeric, cellular myosins-M2A, M2B and M2C-participate in diverse roles including, but not limited to: neuronal dynamics, axon guidance and synaptic transmission; endothelial cell migration; cell adhesion, polarity, fusion and cytokinesis; vesicle trafficking and viral egress. These three conventional myosins each take on specific, differing functional roles during development and maturity, characteristic of each cell lineage; exact roles depend on the developmental stage of the cell, cellular location, upstream regulatory controls, relative isoform expression, orientation and associated state of the actin cytoscaffolds in which these myosins operate. Here, we discuss the separate yet related roles that characterise the actions of M2A, M2B and M2C in various cell types and show that these conventional myosins are responsible for functions as unconventional as any performed by unconventional myosins.

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S100A4, a Mediator of Metastasis

Cited by 315 publications

References 81 publications

Dual role of the ddx5/ddx17 RNA helicases in the control of the pro-migratory NFAT5 transcription factor

Dual role of the ddx5/ddx17 RNA helicases in the control of the pro-migratory NFAT5 transcription factor

Interaction of extracellular S100A4 with RAGE prompts prometastatic activation of A375 melanoma cells

Conventional myosins – unconventional functions

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