Granulin-epithelin precursor interacts with heparan sulfate on liver cancer cells.

Abstract

Granulin-epithelin precursor (GEP) is a pluripotent secretory growth factor which promotes cancer progression in a number of human cancers. However, how cancer cells interact with GEP remains unknown. In this study, we aimed to identify the cell surface-binding partner of GEP on liver cancer cells. Human recombinant GEP (rGEP) was expressed and purified to homogeneity. The rGEP was shown to trigger phosphorylation of AKT and ERK1/2 in liver cancer cells. We demonstrated cell surface attachment of rGEP, which was blocked by prebinding of platelet-derived growth factor-AA, platelet-derived growth factor-BB and fibroblast growth factor-2. Therefore, heparan sulfate (HS) had been reasoned as the binding partner of rGEP. Heparinase digestion validated the role of HS on supporting the attachment. The heparin-binding domain of GEP was mapped to RRH(555-557) in the C-terminal region. Suppression of the HS polymerase exostosin-1 reduced the rGEP binding and rGEP-mediated signaling transduction. Suppression of a specific HS proteoglycan, glypican-3, also showed a partial reduction of rGEP binding and an inhibition on rGEP-mediated activation of AKT. Furthermore, glypican-3 was shown to correlate with the expressions of GEP in clinical samples (Spearman's ρ = 0.363, P = 0.001). This study identified HS, partly through glypican-3, as a novel binding partner of GEP on the surface of liver cancer cells.

• Authors: Chi Wai Yip, Phyllis F Y Cheung, Idy C Y Leung, Nicholas C L Wong, Christine K C Cheng, Sheung Tat Fan, Siu Tim Cheung
• Journal: Carcinogenesis (Carcinogenesis) Vol. 35 Issue 11 Pg. 2485-94 (Nov 2014) ISSN: 1460-2180 [Electronic] England
• PMID: 25115442 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2014. Published by Oxford University Press.

Chemical References

• GRN protein, human
• Glypicans
• Intercellular Signaling Peptides and Proteins
• Progranulins
• Fibroblast Growth Factor 2
• Heparitin Sulfate
• Oncogene Protein v-akt

Topics

• Carcinoma, Hepatocellular (genetics, pathology)
• Fibroblast Growth Factor 2 (biosynthesis, genetics)
• Gene Expression Regulation, Neoplastic
• Glypicans (antagonists & inhibitors, metabolism)
• Hep G2 Cells
• Heparitin Sulfate (genetics, metabolism)
• Humans
• Intercellular Signaling Peptides and Proteins (biosynthesis, genetics)
• Liver Neoplasms (genetics, metabolism)
• MAP Kinase Signaling System (genetics)
• Oncogene Protein v-akt (genetics)
• Progranulins
• Protein Binding