GITR/GITRL reverse signalling modulates the proliferation of hepatic progenitor cells by recruiting ANXA2 to phosphorylate ERK1/2 and Akt.

Abstract

Hepatic stem/progenitor cells are the major cell compartment for tissue repair when hepatocyte proliferation is compromised in chronic liver diseases, but the expansion of these cells increases the risk of carcinogenesis. Therefore, it is essential to explore the pathways restricting their expansion and abnormal transformation. The ligand of glucocorticoid-induced tumour necrosis factor receptor (GITRL) showed the most highly increased expression in hepatic progenitor cells treated with transforming growth factor (TGF)-β1. If overexpressed by hepatic progenitor cells, GITRL stimulated cell proliferation by activating the epithelial-mesenchymal transition pathway and enhancing ERK1/2 and Akt phosphorylation via GITRL binding to ANXA2. However, GITR, the specific GITRL receptor, suppressed the epithelial-mesenchymal transition pathway of GITRL-expressing cells and decreased their growth by dissociating ANXA2 from GITRL and reducing downstream ERK1/2 and Akt phosphorylation. This study identifies GITR/GITRL reverse signalling as a cross-interaction pathway between immune cells and hepatic stem/progenitor cells that restricts the expansion of hepatic stem/progenitor cells and reduces the possibility of carcinogenesis.

• Authors: Yu He, Yufeng Pei, Kai Liu, Lin Liu, Yue Tian, Hongyi Li, Min Cong, Tianhui Liu, Hong Ma, Hong You, Jidong Jia, Dong Zhang, Ping Wang
• Journal: Cell death & disease (Cell Death Dis) Vol. 13 Issue 4 Pg. 297 (04 04 2022) ISSN: 2041-4889 [Electronic] England
• PMID: 35379781 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• ANXA2 protein, human
• Annexin A2
• Glucocorticoid-Induced TNFR-Related Protein
• Tumor Necrosis Factors
• Proto-Oncogene Proteins c-akt

Topics

• Annexin A2 (metabolism)
• Carcinogenesis
• Cell Proliferation
• Glucocorticoid-Induced TNFR-Related Protein (genetics, metabolism)
• Humans
• MAP Kinase Signaling System
• Proto-Oncogene Proteins c-akt (metabolism)
• Stem Cells (metabolism)
• Tumor Necrosis Factors (metabolism)