TAM receptors and the clearance of apoptotic cells

Abstract

The Tyro3, Axl, and Mer (TAM) receptor tyrosine kinases and their ligands Gas6 and Protein S are required for the optimal phagocytosis of apoptotic cells in the mature immune, nervous, and reproductive systems. Genetic analyses in mice, rats, and humans reveal that this receptor-ligand system plays an especially important role in the phagocytosis that is triggered by the "eat-me" signal phosphatidylserine. Deficiencies in TAM signaling lead to human retinal dystrophies and may contribute to lupus and other human autoimmune diseases. The TAM system appears to interact and cooperate with several other phagocytic networks, including scavenger receptor and integrin-based systems, and may serve as a signaling hub that integrates these systems.

Figure 1

The three TAM receptors and their two ligands. Tyro3, Axl, and Mer (officially c-Mer) are receptor protein-tyrosine kinases (red) expressed by dendritic cells, macrophages, immature NK cells of the immune system, Sertoli cells of the testis, retinal pigment epithelial (RPE) cells of the eye, endothelial cells of the vasculature, and other cells. Older alternative names for each receptor are also indicated. (The corresponding NCBI gene names are Tyro3, Axl, and Mertk.) TAM receptor dimers bind to their two ligands, Gas6 and Protein S (green), through interaction between the two N terminal Ig domains of the receptors and the two C terminal laminin G (LG) regions—which together make up the “SHBG domain”—of the ligands. Through their N terminal Gla domains, Gas6 and ProS bind to phosphatidylserine, which is displayed on the extracellular surface of apoptotic cells and on photoreceptor (PR) outer segments. These Gla domains require vitamin K–dependent γ-carboxylation of glutamic acid residues for full TAM ligand bioactivity. Adapted from Lemke and Rothlin.