| MERTK is a type I receptor tyrosine kinase of the TAM family (with TYRO3 and AXL) that is expressed on myeloid cells, retinal pigment epithelium, and selected epithelial and tumor cells, where it integrates ligand binding with efferocytosis and survival signaling. The receptor has an extracellular region composed of immunoglobulin‑like and fibronectin type III domains that bind vitamin K–dependent ligands such as Gas6 and Protein S on phosphatidylserine‑exposed apoptotic cells, a single transmembrane helix, and an intracellular kinase domain with multiple tyrosine residues that act as docking sites once phosphorylated. Ligand engagement on apoptotic cell surfaces induces MERTK dimerization and autophosphorylation, which recruits adaptor proteins including GRB2 and PLCG2 and activates canonical pathways such as RAS–RAF–MEK–ERK, PI3K–AKT, and JAK–STAT, leading to increased expression or activation of prosurvival and motility‑associated effectors including BCL‑2, survivin, focal adhesion kinase, and myosin light chain 2. These signaling outputs couple recognition of apoptotic targets to cytoskeletal reorganization and engulfment during efferocytosis, while at the same time supporting cell survival and limiting inflammatory responses in macrophages and other MERTK‑positive immune cells. In dendritic cells and macrophages, MERTK activation also upregulates SOCS1 and SOCS3 and dampens Toll‑like receptor signaling through STAT1‑dependent mechanisms, providing a negative feedback loop that constrains cytokine production and contributes to peripheral tolerance to self‑antigens derived from apoptotic cells. Genetic disruption of Mertk in mouse models impairs apoptotic cell clearance and leads to loss of apoptotic cell–induced T‑cell tolerance, with accumulation of autoreactive lymphocytes and development of systemic autoimmunity. On malignant cells, aberrant or ectopic MERTK expression is reported across acute leukemias, non‑small cell lung cancer, glioblastoma, melanoma, and several solid tumors, where sustained activation of MAPK and PI3K–AKT downstream of the receptor decreases apoptosis, enhances migration and invasion, promotes chemoresistance, and supports clonogenic and tumor‑forming capacity in preclinical models. |
