Gas6 can bind to all three of the TAM receptors, while ProS only binds to Tyro3 and Mer. The SHBG domain has two globular laminin G-like domains and mediates ligand-receptor binding. The two ligands have a similar domain structure, with an N-terminal γ-carboxyglutamic acid domain that mediates Ca 2+-dependent binding to a negative charge phosphatidylserine (PtdSer)-presenting membrane, a loop-region, four epidermal growth factor (EGF)-like repeats, and a C-terminal sex hormone-binding globulin (SHBG) domain. The two best characterized TAM ligands are the vitamin K-dependent proteins growth arrest-specific 6 (Gas6) and protein S (ProS). The unique conserved sequence KW(I/L)A(I/L)ES in the kinase domain and the unique configuration of two immunoglobulin-like and two fibronectin type III domains within the extracellular domain distinguish TAM receptors from other RTKs. Structure of TAM Receptors and Their LigandsĪll RTKs, including the TAM receptors, have an extracellular domain, a transmembrane domain, and a conserved intracellular kinase domain. We provide a description of the pathways involved in the different diseases, the role of TAM receptor deregulation in disease therapy, and, finally, strategies that target TAM receptors.Ģ. We explore the deregulation of TAM receptors in the autoimmune diseases and in cancer. In this review we will discuss the biological function of TAM receptors and their ligands. In cancer, overexpression of TAM receptors has been associated with chemo-resistance, metastasis, and poor survival outcomes. TAM receptors have been reported to play a role in a broad spectrum of human autoimmune disorders such as rheumatoid arthritis, multiple sclerosis (MS), and systemic lupus erythematosus (SLE), as well in cancer (reviewed in ). These include the mature immune, hematopoietic, nervous, vascular, and reproductive systems. Conversely, in all adult knockouts (even single knockouts), mice show a multitude of irregularities, indicating an essential role in maintenance and homeostatic balance in a wide variety of mature organ systems that are subjected to renewal throughout adult life.
In mice, TAM receptors have no essential embryonic function, since single-, double-, and even triple-knockout mice are viable, showing no obvious development defects at birth. The TAM family of RTKs has three members: Tyro3, Axl, and Mer. Receptor tyrosine kinases (RTKs) regulate normal cellular processes, including growth, survival, differentiation, motility, and adhesion by converting signals from the extracellular environment to the cytoplasm and nucleus.