Extracellular AGR2 activates neighboring fibroblasts through endocytosis and direct binding to β-catenin that requires AGR2 dimerization and adhesion domains

Anterior gradient 2 (AGR2) is often overexpressed in several types of cancer. AGR2 is cytoplasmic or secreted as an extracellular signal. Intracellular AGR2 properties and role in cancer have been well studied, but its extracellular function is largely unclear. It has been shown that extracellular A...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Biochemical and biophysical research communications 2021-10, Vol.573, p.86-92
Hauptverfasser: Merugu, Siva Bharath, Zhou, Bingjie, Mangukiya, Hitesh Bhagavanbhai, Negi, Hema, Ghulam, Raza, Roy, Debmalya, Qudsia, Sehar, Wang, Zeling, Mashausi, Dhahiri Saidi, Yunus, Fakhar-Un-Nisa, Liu, Guo-Song, Li, Dawei
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung:Anterior gradient 2 (AGR2) is often overexpressed in several types of cancer. AGR2 is cytoplasmic or secreted as an extracellular signal. Intracellular AGR2 properties and role in cancer have been well studied, but its extracellular function is largely unclear. It has been shown that extracellular AGR2 activates endothelial cells and fibroblasts in culture, but the mechanism of AGR2 signaling is not well elucidated. Here, we report that tumor secreted or externally added AGR2 translocates into cytoplasm by endocytosis, binds to β-catenin and further co-translocates to the nucleus in NIH3T3 fibroblasts. Externally added AGR2 also increased β-catenin expression, stability, and accumulation in the nucleus in both fibroblasts and cancer cells. External AGR2 rescued the expression of β-catenin, which was suppressed by EGFR inhibitor AG1478 indicating an alternative pathway to regulate β-catenin independent of EGFR signal. These effects were abolished when a monoclonal antibody against AGR2 was added to the experiments, confirming the effects are caused by AGR2 only. Putting together, our results show that extracellular AGR2 signaling pathway involves endocytosis mediated cellular translocation, direct binding and regulating β-catenin nuclear accumulation. It is also a target against tumor initiated AGR2 signaling to form and maintain tumor microenvironment. •AGR2 is internalized and translocated to nucleus in fibroblasts via endocytosis.•AGR2 need dimer and adhesion domain for efficient internalization and translocation.•Both intracellular and extracellular AGR2 binds to β-catenin.•AGR2 stabilizes and accumulates β-catenin in the nucleus.•Antibody against AGR2, 18A4 inhibits these functional properties.
ISSN:0006-291X
1090-2104
1090-2104
DOI:10.1016/j.bbrc.2021.08.028