Alternative titles; symbols
HGNC Approved Gene Symbol: TYRO3
Cytogenetic location: 15q15.1 Genomic coordinates (GRCh38): 15:41,559,212-41,583,589 (from NCBI)
Polvi et al. (1993) cloned partial cDNAs of the human TYRO3 gene and its processed pseudogene (TYRO3P) from human teratocarcinoma cell, bone marrow, and melanocyte cDNA libraries. The tyrosine kinase homologous domains of the 2 genes were sequenced and compared with each other and with the mouse Tyro3 gene. Abundant levels of the 4.2-kb TYRO3 mRNA were detected in human brain, with lower levels in other human tissues.
Polvi et al. (1993) assigned the TYRO3 and TYRO3P genes to human chromosome 15q14-q25 by analysis of DNAs from somatic cell hybrids. Richard et al. (1994) used PCR to map 149 chromosome 15 loci with respect to chromosome breakpoints which divided chromosome 15 into 5 regions. The TYRO3 gene was mapped to region III, which extended from chromosome 15q15.1 to 15q21.1.
Gross (2016) mapped the TYRO3 gene to chromosome 15q15.1 based on an alignment of the TYRO3 sequence (GenBank BC049368) with the genomic sequence (GRCh38).
Richard and Beckmann (1996) found that Tyro3 in the mouse is closely linked to Canp3 (114240), which appeared to be located on mouse chromosome 2. Liao et al. (1996) localized the Tyro3 gene to mouse chromosome 2, closely linked to Ltk (151520).
Loss of function of the 3 TAM receptors, Tyro3, Axl (109135), and Mer (MERTK; 604705), results in profound dysregulation of the immune response in mice (see ANIMAL MODEL). By analyzing TAM function in the dendritic cell subset of mouse antigen-presenting cells, Rothlin et al. (2007) found that TAM inhibited inflammation through an essential stimulator of inflammation, Ifnar (107450), and its associated transcription factor, Stat1 (600555). Toll-like receptor (TLR; see 601194) induction of Ifnar-Stat1 signaling upregulated the TAM system, which, in turn, induced the cytokine and TLR suppressors Socs1 (603597) and Socs3 (604176). Rothlin et al. (2007) concluded that cytokine-dependent activation of TAM signaling diverts a proinflammatory pathway to provide an intrinsic feedback inhibitor of both TLR- and cytokine-driven immune responses.
Paolino et al. (2014) demonstrated that genetic deletion of the E3 ubiquitin ligase CBLB (604491) or targeted inactivation of its E3 ligase activity licenses natural killer (NK) cells to spontaneously reject metastatic tumors. The TAM tyrosine kinase receptors TYRO3, AXL, and MERTK were identified as ubiquitylation substrates for CBLB. Treatment of wildtype NK cells with a small molecule TAM kinase inhibitor conferred therapeutic potential, efficiently enhancing antimetastatic NK cell activity in vivo. Oral or intraperitoneal administration using this TAM inhibitor markedly reduced murine mammary cancer and melanoma metastases dependent on NK cells. Paolino et al. (2014) further reported that the anticoagulant warfarin exerts antimetastatic activity in mice via Cblb/TAM receptors in NK cells, providing a molecular explanation for the effect of warfarin to reduce tumor metastases in rodent models. Paolino et al. (2014) concluded that this novel TAM/CBLB inhibitory pathway shows that it might be possible to develop a 'pill' that awakens the innate immune system to kill cancer metastases.
By performing a metaanalysis of 3 independent genomewide association studies of Latino and African Americans with asthma (see 600807), Chan et al. (2016) identified several intronic variants in TYRO3 that were associated with asthma, including a SNP located within several putative transcription factor binding sites. Based on sequence similarity with AXL and MERTK, the authors hypothesized that TYRO3 may limit the magnitude of the type-2 immune response. They found that circulating CD11C (ITGAX; 151510)-high/CD11B (ITGAM; 120980)-low dendritic cells (DCs) of helminth-infected patients had increased TYRO3 expression. Mixed lymphocyte responses in the presence of anti-TYRO3 resulted in a significant increase in IL13 (147683), but not IFNG (147570), indicating that TYRO3 has a selective inhibitory role in type-2, but not type-1, immunity. In light of additional studies in mice (see ANIMAL MODEL), Chan et al. (2016) concluded that the TYRO3-PROS1 (176880) axis is an evolutionarily conserved negative regulator of the magnitude of the type-2 immune response.
Regulation of lymphocyte numbers is mediated by cytokines signaling through receptors coupled to cytoplasmic protein-tyrosine kinases. Lu and Lemke (2001) generated mice deficient in Mertk (604705), Axl (109135), and Tyro3. Like their ligands, GAS6 (600441) and PROS1, these receptors are widely expressed in monocytes and macrophages but not in B or T lymphocytes. Although the peripheral lymphoid organs of mutant mice were indistinguishable from those of wildtype mice at birth, by 4 weeks of age spleens and lymph nodes grew at elevated rates. This was primarily due to the hyperproliferation of constitutively activated B and T cells, particularly CD4-positive T cells, with ectopic colonies in every adult organ examined. All triple mutants developed autoimmunity with symptoms histologically similar to human rheumatoid arthritis (180300), pemphigus vulgaris (169610), and systemic lupus erythematosus (152700), and were characterized by antibodies against normal cellular antigens, including phospholipids and double-stranded DNA. Females were particularly prone to thromboses and recurrent fetal loss. Flow cytometric analysis demonstrated that wildtype B and T cells underwent multiple rounds of cell division after injection into mutant mice and that their antigen-presenting cells expressed elevated levels of activation markers. Lu and Lemke (2001) proposed that the cells that initiate lymphoproliferation and autoimmunity in the Tyro3 family mutants were the macrophages and dendritic cells that normally express the 3 receptor genes.
Angelillo-Scherrer et al. (2005) generated mice lacking 1 of the 3 Gas6 receptors: Tyro3, Axl, or Mertk. Loss of any 1 of the Gas6 receptors or delivery of a soluble extracellular domain of Axl that traps Gas6 protected the mice against life-threatening thrombosis. Loss of a Gas6 receptor did not prevent initial platelet aggregation but impaired subsequent stabilization of platelet aggregates, at least in part by reducing outside-in signaling and platelet granule secretion. Gas6, through its receptors, activated PI3K and Akt (see 164730) and stimulated tyrosine phosphorylation of the beta-3 integrin (173470), thereby amplifying outside-in signaling via alpha-IIb (607759)-beta-3.
Using the house dust mite (HDM) mouse model of asthma, Chan et al. (2016) showed that mice lacking Tyro3 and sensitized with HDM had increased numbers of leukocytes and eosinophils in lungs and bronchoalveolar lavage fluid, as well as increased Cd4-positive T cells in mediastinal lymph nodes producing Il4 (147780) and Il13, but not Ifng, compared with wildtype mice. Serum IgE levels were also higher in HDM-sensitized Tyro3 -/- mice compared with wildtype mice. The exacerbated cellular and humoral responses in Tyro3 -/- mice correlated with increased lung pathology. Tyro3-/- mice showed enhanced immunity and clearance of Nippostrongylus brasiliensis (Nb) worms from lungs and small intestine, but not skin. Tyro3 expression was increased in lung DCs, but not in alveolar macrophages, eosinophils, or neutrophils, of HDM-sensitized or Nb-infected mice. Pros1 -/- mice showed the same phenotype as Tyro3 -/- mice. Chan et al. (2016) concluded that PROS1-mediated feedback from adaptive immunity engages TYRO3 on innate immune cells to limit the intensity of type-2 responses.
Angelillo-Scherrer, A., Burnier, L., Flores, N., Savi, P., DeMol, M., Schaeffer, P., Herbert, J.-M., Lemke, G., Goff, S. P., Matsushima, G. K., Earp, H. S., Vesin, C., Hoylaerts, M. F., Plaisance, S., Collen, D., Conway, E. M., Wehrle-Haller, B., Carmeliet, P. Role of Gas6 receptors in platelet signaling during thrombus stabilization and implications for antithrombotic therapy. J. Clin. Invest. 115: 237-246, 2005. [PubMed: 15650770] [Full Text: https://doi.org/10.1172/JCI22079]
Chan, P. Y., Carrera Silva, E. A., De Kouchkovsky, D., Joannas, L. D., Hao, L., Hu, D., Huntsman, S., Eng, C., Licona-Limon, P., Weinstein, J. S., Herbert, D. R., Craft, J. E., Flavell, R. A., Repetto, S., Correale, J., Burchard, E. G., Torgerson, D. G., Ghosh, S., Rothlin, C. V. The TAM family receptor tyrosine kinase TYRO3 is a negative regulator of type 2 immunity. Science 352: 99-103, 2016. [PubMed: 27034374] [Full Text: https://doi.org/10.1126/science.aaf1358]
Gross, M. B. Personal Communication. Baltimore, Md. 9/6/2016.
Liao, X., Zhou, R., Gilbert, D. J., Copeland, N. G., Jenkins, N. A. Receptor tyrosine kinase gene Tyro3 maps to mouse chromosome 2, closely linked to Ltk. Mammalian Genome 7: 395-396, 1996. [PubMed: 8661736] [Full Text: https://doi.org/10.1007/s003359900116]
Lu, Q., Lemke, G. Homeostatic regulation of the immune system by receptor tyrosine kinases of the Tyro 3 family. Science 293: 306-311, 2001. [PubMed: 11452127] [Full Text: https://doi.org/10.1126/science.1061663]
Paolino, M., Choidas, A., Wallner, S., Pranjic, B. Uribesalgo, I., Loeser, S., Jamieson, A. M., Langdon, W. Y., Ikeda, F., Fededa, J. P., Cronin, S. J., Nitsch, R., and 12 others. The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells. Nature 507: 508-512, 2014. [PubMed: 24553136] [Full Text: https://doi.org/10.1038/nature12998]
Polvi, A., Armstrong, E., Lai, C., Lemke, G., Huebner, K., Spritz, R. A., Guida, L. C., Nicholls, R. D., Alitalo, K. The human TYRO3 gene and pseudogene are located in chromosome 15q14-q25. Gene 134: 289-293, 1993. [PubMed: 8262388] [Full Text: https://doi.org/10.1016/0378-1119(93)90109-g]
Richard, I., Beckmann, J. S. Molecular cloning of mouse canp3, the gene associated with limb-girdle muscular dystrophy 2A in human. Mammalian Genome 7: 377-379, 1996. [PubMed: 8661728] [Full Text: https://doi.org/10.1007/s003359900108]
Richard, I., Broux, O., Chiannilkulchai, N., Fougerousse, F., Allamand, V., Bourg, N., Brenguier, L., Devaud, C., Pasturaud, P., Roudaut, C., Lorenzo, F., Sebastiani-Kabatchis, C., Schultz, R. A., Polymeropoulos, M. H., Gyapay, G., Auffray, C., Beckmann, J. S. Regional localization of human chromosome 15 loci. Genomics 23: 619-627, 1994. [PubMed: 7851890] [Full Text: https://doi.org/10.1006/geno.1994.1550]
Rothlin, C. V., Ghosh, S., Zuniga, E. I., Oldstone, M. B. A., Lemke, G. TAM receptors are pleiotropic inhibitors of the innate immune response. Cell 131: 1124-1136, 2007. [PubMed: 18083102] [Full Text: https://doi.org/10.1016/j.cell.2007.10.034]