Lysophosphatidic acid stimulates thrombomodulin lectin-like domain shedding in human endothelial cells.
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.
Wu
Hua-Lin
HL
Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan, ROC.
Lin
Chi-Iou
CI
Huang
Yuan-Li
YL
Chen
Pin-Shern
PS
Kuo
Cheng-Hsiang
CH
Chen
Mei-Shing
MS
Wu
Georgiana Cho-Chen
GC
Shi
Guey-Yueh
GY
Yang
Hsi-Yuan
HY
Lee
Hsinyu
H
D001665:Binding Sites; D002460:Cell Line; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D066246:ErbB Receptors / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D037102:Lectins / Q000378:metabolism*; D008246:Lysophospholipids / Q000494:pharmacology*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D018180:Thrombomodulin / Q000378:metabolism*
D037102:Lectins; D008246:Lysophospholipids; D018180:Thrombomodulin; D066246:ErbB Receptors; D020782:Matrix Metalloproteinases; C032881:lysophosphatidic acid