MERTK (myeloid-epithelial-reproductive tyrosine kinase) is a receptor tyrosine kinase (RTK) that belongs to the TAM (Tyro3, Axl, and Mertk) family of receptor tyrosine kinases. It is highly expressed in monocytes/macrophages, testis, and epithelial cells, including the retinal pigment epithelium (RPE). Physiologically, MERTK is centrally involved in regulating tissue homeostasis and repair as well as innate immune control. It plays a crucial role in mediating efferocytosis by monocyte-derived immune cells, such as macrophages, and by epithelial cells. Efferocytosis is the process by which apoptotic cells are recognized and engulfed by phagocytes, and MERTK's role in this process is critical for preventing the release of damage-associated molecular patterns (DAMPs) into the tissue microenvironment, thus maintaining immunological silence and tissue homeostasis. MERTK's main ligands are Vitamin K-modified endogenous proteins Gas6 and Protein S (ProS1), which bind to MERTK via two carboxyl-terminal laminin-like globular (LG) domains. Recent studies indicate that Vitamin K-dependent γ-carboxylation on the N-terminal Gla domain of Gas6 and Protein S is necessary for phosphatidylserine (PS) binding and MERTK activation, implying that MERTK is preferentially active in tissues where there is high externalized PS, such as the tumor microenvironment (TME) and acute virally infected tissues. In the context of cancer, MERTK can be subverted and contributes to an immune-suppressive microenvironment that promotes cancer growth and progression. It promotes growth factor independence, survival signaling, and tumor cell motility, leading to oncogenic transformation, enhanced tumor growth, therapeutic resistance, and metastasis.
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