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

J 2022

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

BOUCHALOVÁ, Pavla, Lucia SOMMEROVÁ, David POTĚŠIL, Andrea MARTIŠOVÁ, Petr LAPČÍK et. al.

Basic information

Original name

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

Authors

BOUCHALOVÁ, Pavla (203 Czech Republic, belonging to the institution), Lucia SOMMEROVÁ (703 Slovakia), David POTĚŠIL (203 Czech Republic, belonging to the institution), Andrea MARTIŠOVÁ (703 Slovakia, belonging to the institution), Petr LAPČÍK (203 Czech Republic, belonging to the institution), Veronika BRYCHTOVÁ (203 Czech Republic), Alexander SCHERL (756 Switzerland), Petr VOŇKA (203 Czech Republic), Joan PLANAS IGLESIAS (724 Spain, belonging to the institution), Eric CHEVET (250 France), Pavel BOUCHAL (203 Czech Republic, guarantor, belonging to the institution) and Roman HRSTKA (203 Czech Republic)

Edition

Molecular & Cellular Proteomics, American Society for Biochemistry and Molecular Biology, 2022, 1535-9484

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10608 Biochemistry and molecular biology

Country of publisher

Netherlands

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 7.000

RIV identification code

RIV/00216224:14310/22:00125142

Organization unit

Faculty of Science

DOI

http://dx.doi.org/10.1016/j.mcpro.2021.100188

UT WoS

000750798300001

Keywords in English

anterior gradient protein 2; protein-protein interactions; protein disulfide isomerase; mass spectrometry; secretory pathway

Abstract

V originále

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.

Links

LM2018127, research and development project

Name: Česká infrastruktura pro integrativní strukturní biologii (Acronym: CIISB)

Investor: Ministry of Education, Youth and Sports of the CR

MUNI/A/1604/2020, interní kód MU

Name: Podpora biochemického výzkumu v roce 2021

Investor: Masaryk University

NV19-08-00250, research and development project

Name: Proteotypová klasifikace renálního karcinomu ve vztahu k prognóze a terapeutické odpovědi

Investor: Ministry of Health of the CR

90125, large research infrastructures

Name: BBMRI-CZ III

90127, large research infrastructures

Name: CIISB II

Citovat

BOUCHALOVÁ, Pavla, Lucia SOMMEROVÁ, David POTĚŠIL, Andrea MARTIŠOVÁ, Petr LAPČÍK, Veronika BRYCHTOVÁ, Alexander SCHERL, Petr VOŇKA, Joan PLANAS IGLESIAS, Eric CHEVET, Pavel BOUCHAL and Roman HRSTKA. Characterization of the AGR2 Interactome Uncovers New Players of Protein Disulfide Isomerase Network in Cancer Cells. Molecular & Cellular Proteomics. American Society for Biochemistry and Molecular Biology, 2022, vol. 21, No 2, p. 1-19. ISSN 1535-9484. Available from: https://dx.doi.org/10.1016/j.mcpro.2021.100188.

@article{1817657,
   author = {Bouchalová, Pavla and Sommerová, Lucia and Potěšil, David and Martišová, Andrea and Lapčík, Petr and Brychtová, Veronika and Scherl, Alexander and Voňka, Petr and Planas Iglesias, Joan and Chevet, Eric and Bouchal, Pavel and Hrstka, Roman},
   article_number = {2},
   doi = {http://dx.doi.org/10.1016/j.mcpro.2021.100188},
   keywords = {anterior gradient protein 2; protein-protein interactions; protein disulfide isomerase; mass spectrometry; secretory pathway},
   language = {eng},
   issn = {1535-9484},
   journal = {Molecular & Cellular Proteomics},
   title = {Characterization of the AGR2 Interactome Uncovers New Players of Protein Disulfide Isomerase Network in Cancer Cells},
   url = {https://www.sciencedirect.com/science/article/pii/S1535947621001602?via%3Dihub},
   volume = {21},
   year = {2022}
}

TY  - JOUR
ID  - 1817657
AU  - 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
PY  - 2022
TI  - Characterization of the AGR2 Interactome Uncovers New Players of Protein Disulfide Isomerase Network in Cancer Cells
JF  - Molecular & Cellular Proteomics
VL  - 21
IS  - 2
SP  - 1-19
EP  - 1-19
PB  - American Society for Biochemistry and Molecular Biology
SN  - 15359484
KW  - anterior gradient protein 2
KW  - protein-protein interactions
KW  - protein disulfide isomerase
KW  - mass spectrometry
KW  - secretory pathway
UR  - https://www.sciencedirect.com/science/article/pii/S1535947621001602?via%3Dihub
N2  - 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.
ER  -

BOUCHALOVÁ, Pavla, Lucia SOMMEROVÁ, David POTĚŠIL, Andrea MARTIŠOVÁ, Petr LAPČÍK, Veronika BRYCHTOVÁ, Alexander SCHERL, Petr VOŇKA, Joan PLANAS IGLESIAS, Eric CHEVET, Pavel BOUCHAL and Roman HRSTKA. Characterization of the AGR2 Interactome Uncovers New Players of Protein Disulfide Isomerase Network in Cancer Cells. \textit{Molecular \&{} Cellular Proteomics}. American Society for Biochemistry and Molecular Biology, 2022, vol.~21, No~2, p.~1-19. ISSN~1535-9484. Available from: https://dx.doi.org/10.1016/j.mcpro.2021.100188.

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