TAM receptor signaling and phagocytosis

Genetic studies have demonstrated that the TAM system is also required for the phagocytosis of apoptotic cells (ACs) by DCs and macrophages, and that the suppressive effects of ACs on DC and macrophage activation are almost entirely dependent on TAM receptor engagement2-4. TAM receptors are expressed on phagocytes. The TAM ligands Gas6 and Protein S (Pros1) bind to both TAM receptors on the surface of a phagocyte (through a C-terminal domain) and to the phospholipid phosphatidylserine (PtdSer) expressed on the surface of ACs (through an N-terminal ‘Gla domain’.) In this way, Gas6 and Pros1 ‘bridge’ an AC to the phagocyte that will engulf it. TAM action during the phagocytosis of ACs extends to other organ systems, including the nervous and reproductive systems. These activities have broad implications for the use of TAM-based therapies in the treatment of lupus and other autoimmune diseases, which are generally characterized by both chronic inflammation and defects in the phagocytic clearance of ACs. We are currently studying how Tyro3, Axl, and Mer phagocytic activities are differentially controlled by Gas6 and Pros1 in different phagocytes5-7, as well as the interaction of TAM receptors with other phagocytic clearance systems.

2. Lemke, G. and Rothlin, C.V. (2008) Immunobiology of the TAM receptors. Nat. Rev. Immunol. 8: 327-36.
3. Rothlin C.V. and Lemke, G. (2010) TAM receptor signaling and autoimmune disease. Curr. Opin. Immunol. 22: 740-746.
4. Lemke, G. and Burstyn-Cohen, T. (2010) TAM receptors and the clearance of apoptotic cells. Ann. N. Y. Acad. Sci. 1209: 23-29.
5. Zagórska, A., Través, P.G., Lew, E.D., Dransfield, I., and Lemke, G. (2014) Diversification of TAM receptor tyrosine kinase function. Nature Immunology 15: 920-928.
6. Lew, E.D., Oh, J., Burrola, P.G., Lax, I., Zagórska, A., Schlessinger, J., and Lemke, G. (2014) Differential TAM receptor-ligand-phospholipid interactions delimit differential TAM bioactivities. eLife 3. doi: 10.7554/eLife.03385.
7. Dransfield, I., Zagórska, A., Lew, E.D., and Lemke, G. (2015) Mer receptor tyrosine kinase mediates both tethering and phagocytosis of apoptotic cells. Cell Death and Disease: in press.