Lysophosphatidic acid stimulates thrombomodulin lectin-like domain shedding in human endothelial cells
Resource
Biochemical and Biophysical Research Communications 367 (1): 162-168
Journal
Biochemical and Biophysical Research Communications
Journal Volume
367
Journal Issue
1
Pages
162-168
Date Issued
2008
Author(s)
Wu, H.-L.
Lin, C.-I.
Huang, Y.-L.
Chen, P.-S.
Kuo, C.-H.
Chen, M.-S.
Wu, G.C.-C.
Shi, G.-Y.
Yang, H.-Y.
Lee, H.
Abstract
Thrombomodulin (TM) is an anticoagulant glycoprotein highly expressed on endothelial cell surfaces. Increased levels of soluble TM in circulation have been widely accepted as an indicator of endothelial damage or dysfunction. Previous studies indicated that various proinflammatory factors stimulate TM shedding in various cell types such as smooth muscle cells and epithelial cells. Lysophosphatidic acid (LPA) is a bioactive lipid mediator present in biological fluids during endothelial damage or injury. In the present study, we first observed that LPA triggered TM shedding in human umbilical vein endothelial cells (HUVECs). By Cyflow analysis, we showed that the LPA-induced accessibility of antibodies to the endothelial growth factor (EGF)-like domain of TM is independent of matrix metalloproteinases (MMPs), while LPA-induced TM lectin-like domain shedding is MMP-dependent. Furthermore, a stable cell line expressing TM without its lectin-like domain exhibited a higher cell proliferation rate than a stable cell line expressing full-length TM. These results imply that LPA induces TM lectin-like domain shedding, which might contribute to the exposure of its EGF-like domain for EGF receptor (EGFR) binding, thereby stimulating subsequent cell proliferation. Based on our findings, we propose a novel mechanism for the exposure of TM EGF-like domain, which possibly mediates LPA-induced EGFR transactivation. © 2007 Elsevier Inc. All rights reserved.
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