Turnover of thrombomodulin at the cell surface occurs at a similar rate to receptors that are not actively internalized

Loss of thrombomodulin (TM) from the endothelial cell surface is thought to contribute to thrombosis encountered in malignant and inflammatory disease. Internalization or endocytosis of TM from the cell surface has been proposed to be one mechanism by which TM levels are reduced. Previous work has led to a view that TM is rapidly internalized using a non-conventional pathway, under the direction of a signal motif in its extracellular domain. This is contrary to the clathrin-dependent route taken by most rapidly internalized receptors that possess signals in their cytoplasmic domains. However the internalization rate of TM has never been directly compared to known internalizing or non-internalizing molecules. Here we show that the rate and amount of uptake of TM (5-10% per hour) is indistinguishable from the non-internalizing influenza virus haemagglutinin (HA), and is considerably less than the actively internalizing low density lipoprotein receptor, which reaches a steady state of approximately 50% internalized in 15 min. The low level rate of TM and HA internalization observed is comparable to the rate of normal plasma membrane turnover. Furthermore, this uptake of TM does not require a signal in its extracellular domain.