TAM receptor tyrosine kinase family (TAM)

The TAM receptor family consists of three closely related receptor tyrosine kinases: Tyro3, Axl, and MerTK [UniProt: Q06418, P30530, Q12866]. These receptors are characterized by a unique extracellular structure containing two immunoglobulin-like domains and two fibronectin type III domains, which bind to their primary vitamin K-dependent ligands, Gas6 and Protein S [PMID: 23948671]. Biologically, TAM receptors are essential for efferocytosis—the process of clearing apoptotic cells—and act as critical negative regulators of the innate immune response by inhibiting Toll-like receptor (TLR) and cytokine receptor signaling [PMID: 25264244]. In the context of oncology, TAM receptors, particularly Axl and MerTK, are frequently overexpressed or activated, promoting tumor cell survival, metastasis, and the creation of an immunosuppressive tumor microenvironment [PMID: 27141665]. Consequently, they have emerged as significant therapeutic targets, with various small molecule inhibitors and biologics currently in clinical development to overcome drug resistance and enhance anti-tumor immunity [ClinicalTrials.gov: NCT02488291].

Other names

Tyro3-Axl-MerTK familyTAM subfamily of RTKsTAMRTKTyro3, Axl, and MerTK receptors

Inhibition of the intracellular tyrosine kinase domain to prevent autophosphorylation and downstream signaling (e.g., PI3K/Akt, MAPK/ERK), or competitive blockade of ligand binding (Gas6/PROS1) to the extracellular domain to prevent receptor activation [PMID: 25264244, PMID: 27141665].