Abstract 242: Differential activation of TAM receptors by Gas6 and protein S

Abstract Tyro-3, Axl, and Mertk (abbreviated TAM receptors) comprise a homologous family of type I receptor tyrosine kinases (RTKs) have been shown to have increasingly important roles for both homeostasis, particularly for anti-inflammation and the resolution of inflammation. While previous studies have shown that TAM receptors are differentially expressed on immune cells, surprisingly much less is currently known about the differential functional activities and expression of the major TAM ligands, Growth Arrest Factor-specific gene 6 (Gas6) and Protein S (Pros1), particularly whether they have overlapping or distinct biochemical and cellular functions, and how they regulate the interplay between inflammation and coagulation. To evaluate the functions of Gas6 and Pros1, we first cloned and expressed human proteins for testing on TAM-IFNgR1 reporter cell lines. While both Gas6 and Pros1 require post-translational gamma-carboxylation of their Gla domains for biological activity and binding to phosphatidylserine (PS), they possess differential capacity to bind soluble Axl and C4BP. Moreover, both Gas6 and Pros1 require the 4 tandem EGF-like domains for their activity, and both appear to require extracellular protein disulfide isomerase activity for receptor activation. Taken together, we have identified a novel mechanism for TAM activation by Gas6 and Pros1, as well as both overlapping and non-overlapping activities with respect to ligand-dependent receptor activation. These results have potential implications in both cancer and inflammation. Citation Format: Ziren Wang, Samhita Bapat, Varsha Gadiyar, Christopher Varsanyi, Rachael Pulica, Trevor Frederick, Ahmed Aquib, Raymond Birge. Differential activation of TAM receptors by Gas6 and protein S [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 242.