Hemostasis and Beyond: The Diverse Functions of Protein S in Controlling Coagulation, Inflammation, and Cancer

Protein S (ProS) is a vitamin K-dependent glycoprotein that was first described as an anticoagulant cofactor for activated protein C (APC). Since its initial discovery, studies of ProS have revealed an array of functions, spanning coagulation and inflammation, including in the context of cancer. ProS is now known to inhibit all three coagulation complexes—through interactions with APC, tissue factor pathway inhibitor, and activated factor IX—and to have its anticoagulant activity modulated by multiple other plasma proteins. Beyond hemostasis, ProS also participates in complement regulation, through its interaction with complement component C4b-binding protein, and regulates inflammatory cell phenotype and function, through Tyro3 and Mer-Tyrosine Kinase, receptors which mediate efferocytosis, inflammatory resolution, and tissue repair. Emerging evidence further implicates ProS in cancer biology, where its effects are context-dependent and may either support or suppress tumor progression. In this review, we highlight these many functions of ProS and discuss their mechanistic commonalities. Collectively, these functions position ProS as a central regulatory node, with critical roles in physiology and disease.