RAGE Mediates the Pro-Migratory Response of Extracellular S100A4 in Human Thyroid Cancer Cells

Medapati, Manoj Reddy; Dahlmann, Mathias; Ghavami, Saeid; Pathak, Kumar Alok; Lucman, Lydia; Klonisch, Thomas; Hoang‐Vu, Cuong; Stein, Ulrike; Hombach‐Klonisch, Sabine

doi:10.1089/thy.2014.0257

Cited by 29 publications

(29 citation statements)

References 59 publications

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“…The HMGB1-RAGE axis has recently been shown through bioinformatics approaches to be a strong predictor of poor prognosis in lung cancer [72]. Beyond HMGB1, multiple other ligands of RAGE have since been implicated in tumor biology, including S100A4, S100P, S100A12, S100A7, S100A8/9, S100B, S100A14, S100A2, CML-AGE, and lysophosphatidic acid [12, 73–87]. …”

Section: 0 Rage and Cancer – Many Ligands Playing Key Roles In Tummentioning

confidence: 99%

“…To date, in primary murine SMCs, cultured BV2 microglia, human thyroid cancer cells and murine and human macrophages and THP1 cells, small interference RNA-mediated knockdown of Diaph1 or deletion of Diaph1 resulted in significantly reduced signaling in response to RAGE ligands such as S100B, CML-AGE, S100A4 and hypoxia-derived AGEs [73, 92, 124, 125], particularly manifested as reduced activation of Rac1, RhoA and cdc42. In vivo , neointimal expansion in the femoral artery consequent to guide wire induced injury was significantly lower in mice devoid of Diaph1 versus the wild-type control; key roles for RAGE/DIAPH1 signaling in SMCs accounted for these effects [125].…”

Section: 0 Rage Signaling – the Discovery Of The Formin Diaph1 As mentioning

confidence: 99%

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The multiple faces of RAGE – opportunities for therapeutic intervention in aging and chronic disease

Ramasamy

Shekhtman

Schmidt

2015

Expert Opinion on Therapeutic Targets

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Introduction This review focuses on the multi-ligand receptor of the immunoglobulin superfamily, receptor for advanced glycation endproducts (RAGE). The accumulation of the multiple ligands of RAGE in cellular stress milieux links RAGE to the pathobiology of chronic disease and natural aging. Areas Covered In this review, we present a discussion on the ligands of RAGE and the implications of these ligand families in disease. We review the recent literature on the role of ligand-RAGE interaction in the consequences of natural aging; the macro- and microvascular complications of diabetes; obesity and insulin resistance; autoimmune disorders and chronic inflammation; tumors and Alzheimer’s disease. We discuss the mechanisms of RAGE signaling through its intracellular binding effector molecule, the formin DIAPH1. Physico-chemical evidence by which the RAGE cytoplasmic domain binds to the FH1 (formin homology 1) domain of DIAPH1, and the consequences, is also reviewed. Expert Opinion We discuss the modalities of RAGE antagonism currently in pre-clinical and clinical studies. Finally, we present the rationale behind potentially targeting the RAGE cytoplasmic domain-DIAPH1 interaction as a logical strategy for therapeutic intervention in the pathological settings of chronic diseases and aging in which RAGE ligands accumulate and signal.

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Section: 0 Rage and Cancer – Many Ligands Playing Key Roles In Tummentioning

confidence: 99%

Section: 0 Rage Signaling – the Discovery Of The Formin Diaph1 As mentioning

confidence: 99%

The multiple faces of RAGE – opportunities for therapeutic intervention in aging and chronic disease

Ramasamy

Shekhtman

Schmidt

2015

Expert Opinion on Therapeutic Targets

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“…RAGE consists of three extracellular immunoglobulin domains, a V-type Ig domain (residues 23-119) and two C-type Ig domains (C1 and C2) (residues 120-233 and residues 234-325, respectively), a trans-membrane helix, and a short cytoplasmic tail (CT). RAGE signaling plays a central role in the inflammatory response, mediating aspects of immunity, acute and chronic inflammatory disorders, complications of diabetes, and certain cancers (Hofmann et al, 1999; Liliensiek et al, 2004; Medapati et al, 2015; Schmidt et al, 2001; Taguchi et al, 2000; van Zoelen et al, 2009). As a pattern recognition receptor(Xie et al, 2008), RAGE binds diverse families of ligands, including advanced glycation end products (AGEs) (Kislinger et al, 1999; Neeper et al, 1992; Xie et al, 2008; Xue et al, 2011), S100/calgranulins (Hofmann et al, 1999; Koch et al, 2010), High Mobility Group Box-1 (HMGB1)(Taguchi et al, 2000) proteins, amyloid-β peptides (Aβ), β-sheet fibrils (Yan et al, 1996), lysophosphatidic acid (Rai et al, 2012b), and phosphatidylserine (He et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Change in the Molecular Dimension of a RAGE-Ligand Complex Triggers RAGE Signaling

et al. 2016

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Summary The weak oligomerization exhibited by many transmembrane receptors has a profound effect on signal transduction. The phenomenon is difficult to structurally characterize due to the large sizes of and transient interactions between monomers. The receptor for advanced glycation end products (RAGE), a signaling molecule central to the induction and perpetuation of inflammatory responses, is a weak constitutive oligomer. The RAGE domain interaction surfaces that mediate homo-dimerization were identified by combining segmental isotopic labeling of extracellular soluble RAGE (sRAGE) and NMR spectroscopy with chemical crosslinking and mass spectrometry. Molecular modeling suggests that two sRAGE monomers orient head-to-head forming an asymmetric dimer with the C-termini directed towards the cell membrane. Ligand-induced association of RAGE homo-dimers on the cell surface increases the molecular dimension of the receptor, recruiting Diaphanous 1 (DIAPH1) and activating signaling pathways.

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“…Logically, knock down of S100A4 resulted in decreased metastasis formation in a xenografted mouse model of colorectal cancer 11. Very recently, the same group confirmed a similar role of S100A4 in thyroid cancer cells 12. Besides MAPK‐signalling pathways also NF‐κB‐dependent target genes represent potential candidates as mediators of S100A4‐stimulated tumour progression and metastasis in various epithelial and mesenchymal tumour cell lines 13.…”

Section: Introductionmentioning

confidence: 87%

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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RAGE Mediates the Pro-Migratory Response of Extracellular S100A4 in Human Thyroid Cancer Cells

Abstract: The data have identified the RAGE/Dia-1 signaling system as a mediator for the pro-migratory response of extracellular S100A4 in human TC. Thus, therapeutic targeting of the RAGE/Dia-1/small GTPases signaling may successfully reduce local invasion and metastasis in TC.

Cited by 29 publications

References 59 publications

The multiple faces of RAGE – opportunities for therapeutic intervention in aging and chronic disease

The multiple faces of RAGE – opportunities for therapeutic intervention in aging and chronic disease

Change in the Molecular Dimension of a RAGE-Ligand Complex Triggers RAGE Signaling

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

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