Characterization of the AGR2 Interactome Uncovers New Players of Protein Disulfide Isomerase Network in Cancer Cells

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Publikace nespadá pod Lékařskou fakultu, ale pod Přírodovědeckou fakultu. Oficiální stránka publikace je na webu muni.cz.

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BOUCHALOVÁ Pavla SOMMEROVÁ Lucia POTĚŠIL David MARTIŠOVÁ Andrea LAPČÍK Petr BRYCHTOVÁ Veronika SCHERL Alexander VOŇKA Petr PLANAS IGLESIAS Joan CHEVET Eric BOUCHAL Pavel HRSTKA Roman

Rok publikování 2022
Druh Článek v odborném periodiku
Časopis / Zdroj Molecular & Cellular Proteomics
Fakulta / Pracoviště MU

Přírodovědecká fakulta

Citace
www https://www.sciencedirect.com/science/article/pii/S1535947621001602?via%3Dihub
Doi http://dx.doi.org/10.1016/j.mcpro.2021.100188
Klíčová slova anterior gradient protein 2; protein-protein interactions; protein disulfide isomerase; mass spectrometry; secretory pathway
Popis AGR2 is an endoplasmic reticulum (ER)-resident protein disulfide isomerase (PDI) known to be overexpressed in many human epithelial cancers, and is involved in cell migration, cellular transformation, angiogenesis, and metastasis. This protein inhibits the activity of the tumor suppressor p53 and its expression levels can be used to predict cancer patient outcome. However, the precise network of AGR2-interacting partners and clients remains to be fully characterized. Herein, we used label-free quantification and also SILAC-based LC-MS/MS analyses to identify proteins interacting with AGR2. Functional annotation confirmed that AGR2 and its interaction partners are associated with processes in the ER that maintain intracellular metabolic homeostasis and participate in the unfolded protein response, including those associated with changes in cellular metabolism, energy, and redox states in response to ER stress. As a proof of concept, the interaction between AGR2 and PDIA3, another ER resident PDI, was studied in more detail. Pathway analysis revealed that AGR2 and PDIA3 play roles in protein folding in ER, including posttranslational modification and in cellular response to stress. We confirmed the AGR2-PDIA3 complex formation in cancer cells, which was enhanced in response to ER stress. Accordingly, molecular docking characterized potential quaternary structure of this complex, however, it remains to be elucidated whether (i) AGR2 rather contributes to PDIA3 maturation in ER, (ii) the complex directly acts in cellular signaling, or (iii) mediates AGR2 secretion. Our study provides a comprehensive insight into the protein-protein interaction network of AGR2 by identifying functionally relevant proteins and related cellular and biochemical pathways associated with the role of AGR2 in cancer cells.
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