Gas6/TAM Axis in Sepsis: Time to Consider Its Potential Role as a Therapeutic Target

Figure 1

TAM structures and posttranslational regulation. Schematic representation of TAM receptors and their ligands. All TAM receptors share structural domains, i.e., the tyrosine kinase (TK) domain, the transmembrane domain, two fibronectin type III domains (FN III), and two Ig-like domains (Ig) from the C-terminal to the N-terminal (right). The TAM ligands Gas6 and Pros1 share a sex hormone-binding globulin (SHBG) domain and a gamma-carboxyglutamic acid-rich (Gla) domain (right). The Gla domain binds phosphatidylserine (PtdSer) exposed in the outer/external side of the apoptotic cell plasma-membrane, while the SHBG domain interacts with TAM receptor Ig-like domains on the surface of TAM-expressing cells, thus acting as “bridge” proteins (right). The binding itself does not result in receptor activation that occurs through receptor transphosphorylation and in a Ca⁺⁺-dependent fashion (center). For Mer and Axl, the signal transduction is shut down by proteolytic cleavage of the receptor ectodomain (shedding), which is mediated by the transmembrane disintegrin and metalloproteinase (ADAM) 17 and/or ADAM10. Shedding can be induced by inflammatory stimuli (e.g., lipopolysaccharide) leading to the extracellular domain release of the receptor and generating a soluble Axl (sAxl) and soluble Mer (sMer) form able to interact with and sequester the ligands Gas6 and Pros1 (left).