Abstract
The adhesion behavior of human tissue cells changes in vitro, when gravity forces affecting these cells are modified. To understand the mechanisms underlying these changes, proteins involved in cell-cell or cell-extracellular matrix adhesion, their expression, accumulation, localization, and posttranslational modification (PTM) regarding changes during exposure to microgravity were investigated. As the sialylation of adhesion proteins is influencing cell adhesion on Earth in vitro and in vivo, we analyzed the sialylation of cell adhesion molecules detected by omics studies on cells, which change their adhesion behavior when exposed to microgravity. Using a knowledge graph created from experimental omics data and semantic searches across several reference databases, we studied the sialylation of adhesion proteins glycosylated at their extracellular domains with regards to its sensitivity to microgravity. This way, experimental omics data networked with the current knowledge about the binding of sialic acids to cell adhesion proteins, its regulation, and interactions in between those proteins provided insights into the mechanisms behind our experimental findings, suggesting that balancing the sialylation against the de-sialylation of the terminal ends of the adhesion proteins’ glycans influences their binding activity. This sheds light on the transition from two- to three-dimensional growth observed in microgravity, mirroring cell migration and cancer metastasis in vivo.
Highlights
Many types of human tissue cells split into two populations when cultured under simulated or real microgravity conditions
We selected human adhesion proteins, which we found to play a role in experiments when cancer or endothelial cells changed their behavior during exposure to microgravity [5,6,25], and we used the Knowledge Explorer (KE) [43,44], which allows the enrichment of experimental data with knowledge from several fact and reference databases (Figure 1), if the names and related analysis results of the selected proteins were imported via their UniProt accession numbers into an initial resource description framework (RDF) to create a knowledge base (KB) through a combination of semantic protocol and RDF query language (SPARQL) searches across several databases and importing their results iteratively (Figure 1)
The omics network approach described in this paper shows how to gain advantage from combining the results of three different experiments with each other and with the knowledge described in the literature, while focusing on those parts of the data which are related to the topic of cell adhesion
Summary
Many types of human tissue cells split into two populations when cultured under simulated or real microgravity conditions. We subjected thyroid and breast cancer cells and endothelial cells, which had been cultured for a few days on ground, in Space or on a Random Positioning Machine (RPM) simulating microgravity, to mass spectrometry or microarray gene analyses These high throughput omics technologies unveiled thousands of proteins or genes [5,6,7,8], including gravity-sensitive cell adhesion proteins such as integrins, which form alpha-beta dimers [9,10], cadherins [6,11,12], and other cell adhesion molecules [13,14,15] as well as CD44 [16], whose sensitivity to microgravity has repeatedly been described [17]. The results of such analyses have been collected in overview databases such as the UniProt (https://www.uniprot.org/) or dbPTM databases (http://dbptm.mbc.edu.tw) [20] Very often this knowledge is not sufficient, because the biological effect of a protein-bound carbohydrate system is exerted by carbohydrate monomers located at the terminal end of a glycan system consisting of tens or even hundreds of carbohydrate monomers. They are included for comparison and completion purposes, because they are sialylated
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