TYRO3

Tyro3 is a receptor tyrosine kinase that belongs to the TAM family, alongside Axl and MerTK. The human TYRO3 gene encodes a transmembrane protein with an extracellular region containing two immunoglobulin-like domains and two fibronectin type III repeats, and an intracellular tyrosine kinase domain. The receptor is activated by the vitamin K–dependent ligands Gas6 and Protein S (Pros1), which can bridge phosphatidylserine-exposed membranes on apoptotic cells to Tyro3, enabling signal transduction.

Tyro3 is broadly expressed, with notable presence in the nervous system, immune cells such as macrophages and dendritic cells, platelets, and various epithelial and endothelial tissues. Functionally, it promotes efferocytosis—the clearance of apoptotic cells—by phagocytes and helps dampen inflammatory responses by downregulating Toll-like receptor signaling. This contributes to immune tolerance and resolution of inflammation. In the nervous system, Tyro3 participates in signaling that supports neuronal survival and may influence development and glial interactions, although precise roles can vary by cell type and context.

Signaling downstream of Tyro3 commonly engages pathways such as PI3K/Akt and MAPK/ERK, promoting cell survival, migration, and cytoskeletal changes necessary for phagocytosis. Tyro3 activity helps balance immune activation and restraint, with dysregulation linked to disease states.

Clinical relevance is most often discussed in the context of cancer and autoimmune disorders. The Gas6-TYRO3 axis can contribute to tumor cell survival and immune evasion in some cancers, while broader TAM signaling has been implicated in autoimmunity and inflammatory diseases. Targeting TAM receptors, including Tyro3, is an area of active research for therapeutic modulation of immunity and cancer.