The Journey of Protein S from an Anticoagulant to a Signaling Molecule

Protein S (PS), a γ-carboxyglutamate-containing serum protein, was unexpectedly discovered in 1977. Soon after its discovery, PS gained the attention of researchers because of its physiological importance, acting as a multifunctional protein at the intersection of blood coagulation, inflammation, and other cellular processes. Protein S functions as an anticoagulant by directly inhibiting procoagulants, such as Factor Xa (FXa), FVa, and FIXa, while also serving as a cofactor for anticoagulants such as Activated Protein C and Tissue Factor Pathway Inhibitor. By associating with C4b binding protein (C4BP), PS has also been shown to minimize the effect of inflammation. Finally, PS promotes efferocytosis through TAM family protein kinase receptors. Mutations in the PS gene cause pathological conditions such as deep vein thrombosis and hereditary ischemia. In this review, we summarize studies regarding the multiple functions of PS.