"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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