Protein S: a vitamin K-dependent factor bridging haemostasis, tissue homeostasis and cancer

Protein S (PROS1) is a vitamin K-dependent plasma glycoprotein that was originally described as a non-enzymatic cofactor of activated protein C in the regulation of blood coagulation. Over the past three decades, PROS1 has emerged as a pleiotropic signaling molecule with functions that extend far beyond hemostasis. PROS1 is a ligand for the TAM family receptor tyrosine kinases TYRO3 and MERTK and, as such, regulates diverse cellular processes including proliferation, migration, phagocytosis, vascular homeostasis, and immune modulation. These activities are mediated through both circulating and locally produced PROS1 and are pathological context-dependent. In the present review, we first summarize our current knowledge on the regulation of PROS1 gene expression and protein structure. We then discuss its established anticoagulant mechanisms alongside emerging activated protein C-independent functions. Finally, we examine key regulatory roles of protein S-TAM signaling in the vessel wall, central nervous system, inflammation, and cancer. Collectively, these findings position PROS1 as a molecular integrator of coagulation, immunity, and tissue homeostasis and underscore its relevance as both a biomarker and a potential therapeutic target in a broad range of pathophysiological contexts.