Group XIV - Endosialin Family
The endosialin group of CTLD-containing cell surface proteins has three members in both human and mouse: endosialin, CD93, thrombomodulin, and C-type lectin 14A. The extracellular region of each of these type 1 transmembrane proteins consists of a CTLD projected from the cell surface by a Sushi domain, a number of epidermal growth factor (EGF) domains, and a region rich in proline, serine and threonine that carries multiple O-linked glycans. The short cytoplasmic tail often contains tyrosine-based motifs.
Endosialin was originally described as a marker of tumour endothelium, and later as a marker of fibroblasts. It may have a role in angiogenesis and tumour progression. CD93 is expressed on endothelia, myeloid cells, platelets and stem cells. The intracellular domain of CD93 interacts with the cytoskeleton-associated proteins GIPC (GAIP interacting protein, C-terminus) and moesin through charged residues adjacent to the membrane and a PDZ-binding domain at the extreme C-terminus. CD93 triggers phosphoinositide and tyrosine kinase signalling pathways. Cross-linking and inflammatory mediators stimulate CD93 ectodomain shedding and soluble CD93 is found in plasma. There is contradictory evidence concerning the effect of CD93 on Fc receptor- and complement receptor 1-mediated phagocytosis of the pathogen-binding molecules C1q, mannose-binding protein and surfactant protein A. CD93 enhances phagocytosis of apoptotic cells and may mediate intercellular adhesion. Thrombomodulin is an endocytic receptor expressed primarily on endothelial cells. It exerts an anticoagulant effect through the sequestration of thrombin and activation of protein C, which degrades coagulation factors. Thrombin sequestration inhibits activation of the G-protein-coupled protease-activated receptor (PAR)-1. Protein C acts on a variety of other targets, and the thrombomodulin-protein C system is essential for maintaining the placenta during pregnancy. Thrombomodulin influences inflammation and tumour progression and thrombomodulin polymorphisms have been linked to thrombotic conditions such as heart attack. The function of C-type lectin 14A is not known.
It is not known if carbohydrate recognition is involved in the function of proteins in the endosialin group. The CTLDs in these proteins do not contain the sequence motifs connected with sugar-binding activity.
