Apoptotic cell recognition receptors, Tyro3, Axl and Mer, demonstrate distinct patterns of ligand-inducible and ligand-independent receptor activation (P2016)

Abstract

Abstract Proper recognition and removal of apoptotic cells by phagocytes lead to the active suppression of inflammatory responses and the induction of tolerance. Tyro3, Axl and Mer (TAM) receptor tyrosine kinases recognize apoptotic cells through their ligands, Protein S (ProS) and Growth-Arrest-Specific Gene 6 (GAS6), which in turn interact with phosphatidylserine (PS) exposed on the surface of apoptotic cells. Although TAMs share significant similarity, very little is known about the specificity of interaction between TAMs and their ligands, in the context of apoptotic cells, and about downstream signaling cascades triggered through TAMs. To study ligand-receptor interaction, we generated a series of reporter cell lines expressing chimeric TAM receptors that allowed us to demonstrate that each TAM has a unique pattern of interaction with GAS6 and ProS, which is also differentially affected by the presence of apoptotic cells. We also developed another set of chimeric receptors that triggered ligand-independent activation of the TAM intracellular domains, leading to distinct patterns of phosphorylated signaling molecules, as well as different levels of cytokine induction. Overall, these studies suggest that despite their similarity, Tyro3, Axl and Mer are functionally unique in the recognition of apoptotic cells, activation of downstream signaling cascades and gene expression, and therefore, contribute differently to cell survival and the induction of tolerance during tumorigenesis.