Post-translational modifications of the ligands: Requirement for TAM receptor activation

The Tyro3, Axl, and MerTK (TAM) receptors are three homologous Type I Receptor Tyrosine Kinases that have important homeostatic functions in multicellular organisms by regulating the clearance of apoptotic cells (efferocytosis). Pathologically, TAM receptors are overexpressed in a wide array of human cancers, and often associated with aggressive tumor grade and poor overall survival. In addition to their expression on tumor cells, TAMs are also expressed on infiltrating myeloid-derived cells in the tumor microenvironment, where they appear to act akin to negative immune checkpoints that impair host anti-tumor immunity. The ligands for TAMs are two endogenous proteins, Growth Arrest-Specific 6 (Gas6) and Protein S (Pros1), that function as bridging molecules between externalized phosphatidylserine (PtdSer) on apoptotic cells and the TAM ectodomains. One interesting feature of TAMs biology is that their ligand proteins require specific post-translational modifications to acquire activities. This chapter summarized these important modifications and explained the molecular mechanisms behind such phenomenon. Current evidences suggest that these modifications help Gas6/Pros1 to achieve optimal PtdSer-binding capacities. In addition, this chapter included recent discovery of regulating machineries of PtdSer dynamic across the plasma membrane, as well as their potential impacts in the tumor microenvironment. Taken together, this review highlights the importance of the upstream PtdSer and Gas6 in regulating TAMs' function and hope to provide researchers with new perspectives to inspire future studies of TAM receptors in human disease models.