MERTK (UniProt accession Q12866) is a single pass transmembrane receptor that belongs to the TAM (Tyro3, Axl and Mertk) family of receptor tyrosine kinases. MERTK is highly expressed in monocytes/macrophages, testis and epithelial cells including the retinal pigment epithelium (RPE)(Fig. 1A). The human MERTK gene is located on chromosome 2 (2q14. 1) and consists of 19 exons that encode a 999 amino acid protein with a predicted molecular weight of 110 kDa. The actual molecular weight is frequently larger due to N-linked glycosylation.

The MERTK receptor has an extracellular region, with two immunoglobulin-like-C2 (IgG-C2) and two fibronectin type III (FN-III) domains, and an intracellular region that includes a highly conserved tyrosine kinase domain (Fig. 1B). The extracellular region is similar in overall structure to adhesion molecules and binds the vitamin K-dependent modified ligands Gas6 and Protein S (ProS). X-ray crystallographic studies have shown that the IgG-C2 domains mediate binding of Gas6 to the TAM family members Axl and Tyro3. Gas6 also binds to Mertk, although with a lower affinity, presumably by docking with the IgG-C2 domains of the receptor. Both Gas6 and ProS appear to be expressed in the mouse outer retina and recent data indicate that mouse ProS can also activate mouse Mertk. Other results indicate that human ProS does not activate mouse Mertk. Species-specific differences in Mertk binding profiles or a requirement for ProS to bind to heterodimers of TAM receptors are possible explanations for this discrepancy.