title: Lysophosphatidic acid stimulates thrombomodulin lectin-like domain shedding in human endothelial cells.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan, ROC.
authors.forename: Hua-Lin
authors.initials: HL
authors.lastname: Wu
authors.forename: Chi-Iou
authors.initials: CI
authors.lastname: Lin
authors.forename: Yuan-Li
authors.initials: YL
authors.lastname: Huang
authors.forename: Pin-Shern
authors.initials: PS
authors.lastname: Chen
authors.forename: Cheng-Hsiang
authors.initials: CH
authors.lastname: Kuo
authors.forename: Mei-Shing
authors.initials: MS
authors.lastname: Chen
authors.forename: Georgiana Cho-Chen
authors.initials: GC
authors.lastname: Wu
authors.forename: Guey-Yueh
authors.initials: GY
authors.lastname: Shi
authors.forename: Hsi-Yuan
authors.initials: HY
authors.lastname: Yang
authors.forename: Hsinyu
authors.initials: H
authors.lastname: Lee
mesh_terms: 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*
chemical_list: D037102:Lectins; D008246:Lysophospholipids; D018180:Thrombomodulin; D066246:ErbB Receptors; D020782:Matrix Metalloproteinases; C032881:lysophosphatidic acid