Background:The mechanisms by which ligands activate TAM receptors (TYRO3, AXL, and MER) are not well understood. Results:We created a series of TAM reporter cell lines and interrogated ligand-inducible TAM activation. Conclusion: TAMs are differentially activated by GAS6 and protein S and have distinct requirements for phosphatidylserine. Significance: Results reveal molecular mechanisms and rationale for non-overlapping functions of TAMs.

Background: Overexpression of MERTK tyrosine kinase is observed in many human cancers. Results: MERTK has a potent gain-of-function capacity to stimulate efferocytosis in epithelial cells. Conclusion: When overexpressed, MERTK acts as a preeminent efferocytosis receptor that is targetable by soluble Ig-domain containing TAM receptors. Significance: Our findings provide new mechanistic insight into how MERTK may impinge on tumor progression by enhancing efferocytosis.

Receptor tyrosine kinases, Tyro-3, Axl and Mer, collectively designated as TAM, are involved in the clearance of apoptotic cells. TAM ligands, Gas6 and Protein S, bind to the surfaces of apoptotic cells, and at the same time, interact directly with TAM expressed on phagocytes, impacting the engulfment and clearance of apoptotic cells and debris. The well-tuned and balanced actions of TAM may affect a variety of human pathologies including autoimmunity, retinal degeneration, and cancer. This article emphasizes some of the emerging findings and mechanistic insights into TAM functions that are clinically relevant and possibly therapeutically targeted.