The TAM receptor protein tyrosine kinases — TYRO3, AXL and MER — have important roles in the immune, nervous, reproductive and vascular systems. Two closely related proteins — growth-arrest-specific 6 (GAS6) and protein S — function as TAM ligands.
Mutant mice that lack all three TAM receptors are viable, but exhibit a plethora of phenotypes, all of which appear to be degenerative rather than developmental in nature.
Mice deficient in all three TAM receptors develop a severe lymphoproliferative disorder accompanied by broad-spectrum autoimmune disease. These immune phenotypes reflect a loss of TAM function in dendritic cells (DCs), macrophages and natural killer (NK) cells, rather than in lymphocytes.
Recent studies have revealed that autoimmunity in TAM triple mutants results from the loss of TAM-mediated regulation of two phenomena: the inhibition of the innate inflammatory response to pathogens by DCs and macrophages, and the phagocytosis of apoptotic cells by these antigen-presenting cells.
Both TAM-mediated inhibition of inflammation and TAM-mediated stimulation of NK-cell differentiation require an intimate signalling interaction between TAM receptors and cytokine receptors, and this may prove to be a general feature of TAM action in the immune system.
The discovery of TAM receptor function illuminates novel targets for therapeutic intervention. Future studies focused on the selective activation or inhibition of this receptor family may lead to new therapies for chronic inflammatory diseases and new vaccine adjuvants, respectively.
Recent studies have revealed that the TAM receptor protein tyrosine kinases — TYRO3, AXL and MER — have pivotal roles in innate immunity. They inhibit inflammation in dendritic cells and macrophages, promote the phagocytosis of apoptotic cells and membranous organelles, and stimulate the maturation of natural killer cells. Each of these phenomena may depend on a cooperative interaction between TAM receptor and cytokine receptor signalling systems. Although its importance was previously unrecognized, TAM signalling promises to have an increasingly prominent role in studies of innate immune regulation.
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Work in the authors' laboratory is supported by grants from the Lupus Research Institute and the US National Institutes of Health (G.L.), by the Salk Institute (G.L. and C.V.R.) and by the Pew Latin American Fellows Program (C.V.R.).
- Natural killer (NK) cells
NK cells are lymphoid cells capable of lysing bacteria- and virus-infected cells, as well as many tumour cells, without prior sensitization. They have important roles in combating infections, in the immune surveillance of cancer and in host-versus-graft rejection.
- Toll-like receptors
(TLRs). Pattern-recognition receptors that recognize molecules — such as the lipopolysaccharide of bacterial cell walls, the unmethylated CpG-containing deoxynucleotides of bacterial DNA and the double-stranded RNAs of viruses — that are broadly shared by pathogens but not by host cells. Pathogen activation of TLRs initiates the innate immune response in dendritic cells and macrophages.
- SOCS proteins
(Suppressor of cytokine signalling proteins). SOCS proteins inhibit STAT (signal-transducer and activator of transcription) phosphorylation by binding and inhibiting JAKs (Janus-family kinases) and/or competing with STATs for phosphotyrosine binding sites on cytokine receptors. They also inhibit signal transducers downstream of Toll-like receptor activation.
(Signal transducers and activators of transcription). STATs are latent cytoplasmic transcription factors that upon phosphorylation, typically by Janus-family kinases (JAKs), are activated. They then translocate to the nucleus, where they drive the transcription of their target genes. The signal transduction pathways downstream of many cytokine receptors depend on STAT protein activation.
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