MAGP2 induces tumor progression by enhancing uPAR-mediated cell proliferation.

Abstract

Microfibril-associated glycoprotein 2 (MAGP2) plays an important role in regulating cell signaling and acts as a biomarker to predict the prognostic effect of tumor therapy. However, research on MAGP2 mostly focuses on its extracellular signal transmission features, and its potential intracellular function is rarely reported. Here, we reported that intracellular MAGP2 increased the stability of urokinase-type plasminogen activator receptor (uPAR) in the cell by direct interaction which inhibits the lysosomal-mediated degradation of uPAR. Furthermore, with the detection of protein content changes and proteomics analysis, we found that highly expressed MAGP2 promoted the proliferation of tumor cells through uPAR-mediated p38-NF-ĸB signaling axis activation, enhancement of DNA damage repair and reduction of cell stagnation in the S phase of the cell cycle. In the nude mouse xenograft model of colorectal cancer, the upregulation of MAGP2 in tumor cells significantly promoted tumor progression, while the downregulation of uPAR significantly attenuated tumor progression. These studies elucidate the role of MAGP2 inside the cell and provide a new explanation for why patients with higher MAGP2 expression in tumors are associated with a worse prognosis. In addition, we also determined a mechanism for the stable existence of uPAR in the cell, providing information for the development of tumor drugs targeting uPAR.

• Authors: Leyang Wu, Feng Zhou, Wenjie Xin, Lin Li, Lina Liu, Xingpeng Yin, Xuebo Xu, Yao Wang, Zichun Hua
• Journal: Cellular signalling (Cell Signal) Vol. 91 Pg. 110214 (03 2022) ISSN: 1873-3913 [Electronic] England
• PMID: 34915136 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• Contractile Proteins
• Intercellular Signaling Peptides and Proteins
• MFAP5 protein, human
• RNA Splicing Factors
• Receptors, Urokinase Plasminogen Activator
• microfibrillar protein
• Urokinase-Type Plasminogen Activator

Topics

• Animals
• Cell Proliferation
• Contractile Proteins (metabolism)
• Down-Regulation
• Humans
• Intercellular Signaling Peptides and Proteins (metabolism)
• Mice
• Neoplasm Invasiveness
• RNA Splicing Factors (metabolism)
• Receptors, Urokinase Plasminogen Activator (metabolism)
• Signal Transduction
• Urokinase-Type Plasminogen Activator (metabolism)