TAM family receptor tyrosine kinases (TAM RTKs)

The TAM family of receptor tyrosine kinases consists of three members: Tyro3, Axl, and MerTK. These receptors are characterized by a unique extracellular structure containing two immunoglobulin-like domains and two fibronectin type III domains, which bind to their ligands, Growth Arrest-Specific 6 (Gas6) and Protein S (PROS1), in a phosphatidylserine-dependent manner (Lemke, G., 2013, Nature Reviews Immunology). Biologically, TAM receptors are essential for the silent clearance of apoptotic cells (efferocytosis) and act as pleiotropic inhibitors of the innate immune response, particularly by dampening Toll-like receptor (TLR) signaling (Rothlin, C. V., et al., 2007, Cell). In oncology, TAM receptors—especially Axl and MerTK—are frequently upregulated and correlate with poor prognosis, as they promote tumor cell survival, metastasis, and epithelial-to-mesenchymal transition (EMT) (Graham, D. K., et al., 2014, Nature Reviews Cancer). Additionally, they contribute to an immunosuppressive tumor microenvironment by promoting the polarization of M2-like macrophages and inhibiting the maturation of dendritic cells. Consequently, TAM inhibitors are being actively developed as both direct anti-cancer agents and as immune-oncology sensitizers to overcome resistance to checkpoint inhibitors (Myers, S. H., et al., 2019, Journal of Medicinal Chemistry). Beyond cancer, these receptors are implicated in viral entry for viruses like Ebola and Zika, and in autoimmune conditions like systemic lupus erythematosus (NIH, 2023).

Other names

Tyro3, Axl, and MerTK familyTAM receptorsTAM subfamilyTyrosine-protein kinase receptor TYRO3Tyrosine-protein kinase receptor UFOTyrosine-protein kinase receptor Mer

Small molecule inhibition of the intracellular kinase domain to block downstream signaling (PI3K/Akt, MAPK/ERK); monoclonal antibody-mediated blockade of ligand binding; decoy receptor (Axl-Fc) sequestration of ligands.