MERTK

Mer tyrosine kinase (MERTK) is a receptor tyrosine kinase belonging to the TAM family, which also includes TYRO3 and AXL. The human MERTK gene encodes this membrane protein, which is expressed by macrophages, dendritic cells, microglia, and the retinal pigment epithelium, among other cell types. The extracellular portion contains immunoglobulin-like domains and fibronectin type III repeats, followed by a single transmembrane helix and a cytoplasmic tyrosine kinase domain.

MERTK signaling is activated when ligands such as Gas6 or Protein S bind to phosphatidylserine on the surface of apoptotic cells, effectively bridging the victim cell to the receptor. This triggers phagocytosis (efferocytosis) and initiates intracellular cascades involving PI3K/Akt, Rac1, and other pathways that promote cytoskeletal reorganization and clearance of dying cells. Through this process, MERTK supports immune tolerance by limiting inflammatory responses and preventing secondary necrosis.

In the retina, MERTK is essential for the phagocytosis of shed photoreceptor outer segments by the retinal pigment epithelium, a function critical for photoreceptor maintenance. Defects in MERTK can lead to retinal dystrophies, including RP38-like conditions in humans, with progressive vision loss demonstrated in animal models.

Beyond its role in normal physiology, MERTK is implicated in disease contexts such as cancer, where overexpression can promote tumor cell survival and immune evasion. Consequently, selective MERTK inhibitors are being explored in preclinical and clinical studies as potential therapies for cancer and inflammatory diseases.