Thrombomodulin (TM) anchors to vascular endothelial cell membrane with a single transmembranous domain.2,3 It has a large extracellular region that comprises a C-type lectin-like domain at the N-terminus, an epidermal growth factor (EGF)–homology domain that contains 6 EGF-like structures, and a Ser/Thr-rich domain linked to the membrane (see figure). Thrombin and protein C bind to the EGF-homology domain where thrombin cleaves protein C to generate activated protein C (aPC).2 aPC is released into the blood where together with protein S it degrades coagulation factors VIIIa and Va and thereby prevents excessive blood clotting. aPC also possesses anti-inflammatory actions and is effective in controlling inflammatory tissue damage caused by sepsis. Biochemical mechanisms and physiologic roles of TM in coagulation and inflammation have been well characterized.2 However, biochemical characterization has been focused on the thrombin and protein C binding sites at the EGF-homology domain. Little is known about the biologic activity and physiologic role of the C-type lectin-like domain. Kuo and colleagues have generated recombinant TMD1 and used it to probe the biologic activity of the lectin-like domain. They previously reported in Blood that TMD1 binds specifically to LeY and through its binding to Lewis Y epitope on lipopolysaccharide (LPS), it suppresses LPS-induced inflammatory responses.4 Here, Kuo et al provide evidence that recombinant TMD1 controls endothelial cell migration and tube formation through binding to LeY clustered at the endothelial cell membrane ruffles and protrusions.1 Their results show that LeY mediates angiogenesis and TMD1 or LeY antibodies abrogate the angiogenic effect. Epidermal growth factor receptor (EGFR) is expressed on endothelial cell surface. It contains LeY that may be involved in angiogenesis. Investigations in vivo show that TMD1 blocks in vivo angiogenesis induced by EGF and suppresses tumor growth by inhibiting tumor angiogenesis. Taken together, the results indicate that the lectin-like domain of TM is a receptor for LeY that blocks angiogenesis and attenuates inflammatory tissue damage by binding and neutralizing LeY.
