, 2010)—might function differentially as genuine TAM ligands in vivo. The possibility that TAM receptors might act independently

of; that is, without a requirement for, their proposed ligands has also been advanced (Ruan and Kazlauskas, 2012). Our study is the first genetic analysis to address these fundamental questions. We draw five conclusions from our findings. First, Protein S and Gas6 both function as bona fide TAM receptor ligands in vivo in the mouse. Second, either ligand is sufficient to activate Mer and trigger Mer-dependent RPE cell phagocytosis of PR outer segments in the mouse retina. Third, for this process, the two ligands are to a first approximation interchangeable. Fourth, although it may exist, there is no absolute signaling requirement for the formation of a Gas6-Protein S heterodimer. ZD1839 clinical trial Finally, loss of both ligands from the retina phenocopies the loss of Mer, which (1) obviates Selleckchem BKM120 an absolute requirement for a TAM ligand in addition

to Gas6 and Protein S, and (2) also argues against the possibility that Mer function in the eye is TAM-ligand independent. We emphasize that our conclusions on TAM receptor-ligand pairing apply to RPE cells in the retina, and that other cells display different TAM receptor and ligand expression profiles. Macrophages and dendritic cells (DCs) of the immune system, for example, express Axl and Mer, but little or no Tyro3 (Rothlin et al., 2007), while pyramidal neurons of the brain express high levels of Tyro3 but essentially no Axl or Mer (Prieto et al., 2007). Similarly, the diverse populations of TAM-positive cells in the body may be selectively exposed to either Gas6 or Protein S in vivo. In addition to TAM receptor composition, the expression of TAM interacting receptors may also vary between cells, and this may in turn affect the ability of Gas6 or Protein S to activate TAM signaling. RPE cells,

for example, express the αvβ5 integrin, which cooperates with Mer and also plays a role in the circadian RPE phagocytosis of OS membranes (Finnemann and Nandrot, 2006; Nandrot et al., 2008). These points notwithstanding, our results provide a definitive demonstration that Protein S functions as a Mer ligand in the mouse, where it stimulates RPE phagocytosis tuclazepam of OS membranes. Protein S also potently stimulates the phagocytosis of ACs by cultured human macrophages (Anderson et al., 2003; McColl et al., 2009), and Mer is again a key receptor for this process (McColl et al., 2009; Scott et al., 2001). If Mer-expressing macrophages and DCs transit through the blood, they are exposed to the high levels of Protein S (∼300 nM) that are present in the circulation (Burstyn-Cohen et al., 2009; Dahlbäck, 2000). (In contrast, Gas6 is expressed at very low levels [<0.2 nM] in the blood [Ekman et al., 2010].) In tissues, these same cells may be exposed to Protein S produced by activated T cells (Smiley et al., 1997).