Fetuin-A associates with histones intracellularly and shuttles them to exosomes to promote focal adhesion assembly resulting in rapid adhesion and spreading in breast carcinoma cells

Nangami, Gladys N.; Koumangoye, Rainelli; Goodwin, J. Shawn; Sakwe, Amos M.; Marshall, Dana; Higginbotham, James N.; Ochieng, Josiah

doi:10.1016/j.yexcr.2014.08.037

Cited by 34 publications

(52 citation statements)

References 39 publications

(68 reference statements)

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“…These two groups of EV share similarities on the molecular level, therefore it has been suggested that MV are membrane-anchored exosomes (47, 69). In our studies, histone 3a, which has been reported to be present in exosomes (70, 71), was also detected in MV (Fig. 4B).…”

Section: Discussionsupporting

confidence: 79%

Phosphate induces formation of matrix vesicles during odontoblast-initiated mineralization in vitro

et al. 2016

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Mineralization is a process of deposition of calcium phosphate crystals within a fibrous extracellular matrix (ECM). In mineralizing tissues, such as dentin, bone and hypertrophic cartilage, this process is initiated by a specific population of extracellular vesicles (EV), called matrix vesicles (MV). Although it has been proposed that MV are formed by shedding of the plasma membrane, the cellular and molecular mechanisms regulating formation of mineralization-competent MV are not fully elucidated. In these studies, 17IIA11, ST2, and MC3T3-E1 osteogenic cell lines were used to determine how formation of MV is regulated during initiation of the mineralization process. In addition, the molecular composition of MV secreted by 17IIA11 cells and exosomes from blood and B16-F10 melanoma cell line was compared to identify the molecular characteristics distinguishing MV from other EV. Western blot analyses demonstrated that MV released from 17IIA11 cells are characterized by high levels of proteins engaged in calcium and phosphate regulation, but do not express the exosomal markers CD81 and HSP70. Furthermore, we uncovered that the molecular composition of MV released by 17IIA11 cells changes upon exposure to the classical inducers of osteogenic differentiation, namely ascorbic acid and phosphate. Specifically, lysosomal proteins Lamp1 and Lamp2a were only detected in MV secreted by cells stimulated with osteogenic factors. Quantitative nanoparticle tracking analyses of MV secreted by osteogenic cells determined that standard osteogenic factors stimulate MV secretion and that phosphate is the main driver of their secretion. On the molecular level, phosphate-induced MV secretion is mediated through activation of extracellular signal-regulated kinases Erk1/2 and is accompanied by re-organization of filamentous actin. In summary, we determined that mineralization-competent MV are distinct from exosomes, and we identified a new role of phosphate in the process of ECM mineralization. These data provide novel insights into the mechanisms of MV formation during initiation of the mineralization process.

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Section: Discussionsupporting

confidence: 79%

Phosphate induces formation of matrix vesicles during odontoblast-initiated mineralization in vitro

et al. 2016

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“…We previously demonstrated that fetuin‐A in the extracellular milieu promotes rapid uptake of exosomes by cultured tumor cells . In the present studies, we questioned whether exosomal uptake is attenuated in fetuin‐A knocked down glioblastoma cells.…”

Section: Resultsmentioning

confidence: 69%

Fetuin‐A (alpha 2HS glycoprotein) modulates growth, motility, invasion, and senescence in high‐grade astrocytomas

et al. 2016

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Glioblastomas (high‐grade astrocytomas) are highly aggressive brain tumors with poor prognosis and limited treatment options. In the present studies, we have defined the role of fetuin‐A, a liver‐derived multifunctional serum protein, in the growth of an established glioblastoma cell line, LN229. We hereby demonstrate that these cells synthesize ectopic fetuin‐A which supports their growth in culture in the absence of serum. We have demonstrated that a panel of tissue microarray (TMA) of glioblastomas also express ectopic fetuin‐A. Knocking down fetuin‐A using shRNA approach in LN229, significantly reduced their in vitro growth as well as growth and invasion in vivo. The fetuin‐A knockdown subclones of LN229 (A and D) also had reduced motility and invasive capacity. Treatment of LN229 cells with asialofetuin (ASF), attenuated their uptake of labeled fetuin‐A, and induced senescence in them. Interestingly, the D subclone that had ~90% reduction in ectopic fetuin‐A, underwent senescence in serum‐free medium which was blunted in the presence of purified fetuin‐A. Uptake of labeled exosomes was attenuated in fetuin‐A knockdown subclones A and D. Taken together, the studies demonstrate the impact of fetuin‐A as significant node of growth, motility, and invasion signaling in glioblastomas that can be targeted for therapy.

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“…In order to directly implicate histones and fetuin‐A in the uptake mechanisms of hydroxyapatite‐nanoparticles, we reasoned that fetuin‐A which has a high affinity for hydroxyapatite and also associates with positively charged histones could theoretically load histones on hydroxyapatite‐nanoparticles much the same way that it loads histones on exosomes. When fetuin‐A was mixed with the nanoparticles resulting in FN to which cells were added in the wells of 96‐well microtiter plates, the uptake of the particles by PC3 and DU145 cells was negligible (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…We previously proposed that histones/fetuin‐A were the exosomal ligands that interact with cell surface heparan sulfate proteoglycans. These two proteins were abundantly associated with a class of exosomes that were easily taken up by tumor cells . This observation, however, did not rule out the other exosome‐associated proteins such as CD63 and other tetraspanins .…”

mentioning

confidence: 89%

“…The uptake mechanisms of secreted exosomes by recipient cells are just as important and warrant intense investigation. A number of studies have proposed, based on strong experimental evidence, that uptake is primarily mediated by heparan sulfate proteoglycans even though the ligand(s) on exosomes that interact with the heparan sulfate proteoglycans to mediate uptake is yet to be defined. A recent report suggested that fibronectin on exosomes is the ligand that interacts with cell surface heparan sulfate proteoglycans to mediate uptake of the exosomes .…”

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confidence: 99%

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Extracellular histones are the ligands for the uptake of exosomes and hydroxyapatite‐nanoparticles by tumor cells via syndecan‐4

et al. 2018

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The mechanisms by which exosomes (nano-vesicular messengers of cells) are taken up by recipient cells are poorly understood. We hypothesized that histones associated with these nanoparticles are the ligands which facilitate their interaction with cell surface syndecan-4 (SDC4) to mediate their uptake. We show that the incubation with fetuin-A (exosome-associated proteins) and histones mediates the uptake of exosomes that are normally not endocytosed. Similarly, hydroxyapatite-nanoparticles incubated with fetuin-A and histones (FNH) are internalized by tumor cells, while nanoparticles incubated with fetuin-A alone (FN) are not. The uptake of exosomes and FNH, both of which move to the perinuclear region of the cell, is attenuated in SDC4-knockdown cells. Data show that FNH can compete with exosomes for uptake and that both use SDC4 as uptake receptors.

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Fetuin-A associates with histones intracellularly and shuttles them to exosomes to promote focal adhesion assembly resulting in rapid adhesion and spreading in breast carcinoma cells

Cited by 34 publications

References 39 publications

Phosphate induces formation of matrix vesicles during odontoblast-initiated mineralization in vitro

Phosphate induces formation of matrix vesicles during odontoblast-initiated mineralization in vitro

Fetuin‐A (alpha 2HS glycoprotein) modulates growth, motility, invasion, and senescence in high‐grade astrocytomas

Extracellular histones are the ligands for the uptake of exosomes and hydroxyapatite‐nanoparticles by tumor cells via syndecan‐4

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