Growth arrest-specific 6 (Gas6) and Vitamin K-dependent protein S (PROS1) (Gas6 and PROS1)

Growth arrest-specific 6 (Gas6) and Vitamin K-dependent protein S (PROS1) are homologous secreted proteins that serve as the primary ligands for the TAM (Tyro3, Axl, and MerTK) receptor tyrosine kinase family (Graham et al., 2014, Nature Reviews Cancer; Lemke, 2013, Cold Spring Harbor Perspectives in Biology). Gas6 is a universal TAM ligand with the highest affinity for Axl, whereas Protein S is a ligand for Tyro3 and MerTK and also functions as a critical anticoagulant cofactor for activated protein C (Lew et al., 2014, eLife; Dahlbäck, 2018, Journal of Thrombosis and Haemostasis). Both proteins contain a gamma-carboxyglutamic acid (Gla) domain that requires vitamin K for post-translational modification, enabling them to bind to negatively charged phospholipids like phosphatidylserine (Dahlbäck, 2018, Journal of Thrombosis and Haemostasis). These proteins facilitate the recognition and engulfment of apoptotic cells (efferocytosis) by bridging phosphatidylserine on dying cells to TAM receptors on phagocytes, thereby maintaining immune tolerance and preventing autoimmunity (Rothlin et al., 2015, Annual Review of Immunology). In the tumor microenvironment, overproduction of Gas6 and Protein S by cancer cells or infiltrating macrophages leads to constitutive TAM activation, which promotes tumor cell survival, metastasis, and an immunosuppressive milieu (Wu et al., 2018, Cancer Research). Therapeutic targeting of these ligands, particularly through the use of high-affinity decoy receptors like Batiraxcept (AVB-S6-500), aims to sequester the ligands and inhibit cancer progression (Aravive, Inc., 2023, Clinical Trials).

Other names

GAS-6PROS1AXLLGProtein SVitamin K-dependent protein S

Ligand sequestration via decoy receptors to prevent TAM receptor activation; inhibition of gamma-carboxylation to prevent functional protein synthesis.