Alternative titles; symbols
HGNC Approved Gene Symbol: AXL
Cytogenetic location: 19q13.2 Genomic coordinates (GRCh38): 19:41,219,223-41,261,766 (from NCBI)
In an effort to determine genes involved in the progression of chronic myelogenous leukemia (CML; 608232) to acute-phase leukemia, Liu et al. (1988) identified a transforming gene in the DNAs of 2 patients with this disorder. O'Bryan et al. (1991) found by molecular cloning and characterization of this gene, which they termed AXL (from the Greek word 'anexelekto,' or uncontrolled), that it is a receptor tyrosine kinase with a structure novel among tyrosine kinases. They showed that the AXL protein is capable of transforming NIH 3T3 cells. Furthermore, its transforming capacity results from overexpression of AXL mRNA rather than from structural mutation.
Janssen et al. (1991) independently found transforming activity by a tumorigenicity assay using NIH 3T3 cells transfected with DNA from a patient with a chronic myeloproliferative disorder. They reported the cDNA cloning of the corresponding oncogene, which they designated UFO, in allusion to the unidentified function of the protein. Nucleotide sequence analysis revealed a 2,682-bp open reading frame capable of directing the synthesis of an 894-amino acid polypeptide. It was evolutionarily conserved among vertebrate species. The predicted protein showed features characteristic of a transmembrane receptor with tyrosine kinase activity. The gene was transcribed into two 5.0-kb and 3.2-kb mRNAs in human bone marrow and human tumor cell lines.
The transforming activity of AXL demonstrates that the receptor can drive cellular proliferation. Although the function of AXL in nontransformed cells and tissues was unknown, Varnum et al. (1995) suspected that it may involve the stimulation of cell proliferation in response to an appropriate signal, i.e., a ligand that activates the receptor. Varnum et al. (1995) purified an AXL stimulatory factor and identified it as the product of the growth arrest-specific gene-6 (GAS6; 600441) (Manfioletti et al., 1993).
Loss of function of the 3 TAM receptors, Tyro3 (600341), Axl, 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.
Pseudotypes are viral particles that carry the genome of one virus and 1 or more proteins of another virus (Temperton and Wright, 2009). Morizono et al. (2011) studied the infectivity of lentivirus pseudotypes lacking envelope binding and observed residual high infectivity for some cell types. The retained infectivity was conferred by soluble bovine protein S in the culture medium. Morizono et al. (2011) showed that bovine protein S and its human homolog, GAS6, mediated binding of the virus to target cells by bridging virion envelope phosphatidylserine to AXL present on target cells.
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.
Fourgeaud et al. (2016) demonstrated that the TAM receptor tyrosine kinases Mer and Axl regulate the microglial functions of damage sensing and routine noninflammatory clearance of dead brain cells. Fourgeaud et al. (2016) found that adult mice deficient in microglial Mer and Axl exhibit a marked accumulation of apoptotic cells specifically in neurogenic regions of the central nervous system (CNS), and that microglial phagocytosis of the apoptotic cells generated during adult neurogenesis is normally driven by both TAM receptor ligands Gas6 and protein S (176880). Using live 2-photon imaging, the authors demonstrated that the microglial response to brain damage is also TAM-regulated, as TAM-deficient microglia display reduced process motility and delayed convergence to sites of injury. Fourgeaud et al. (2016) also showed that microglial expression of Axl is prominently upregulated in the inflammatory environment that develops in a mouse model of Parkinson disease (168600). Fourgeaud et al. (2016) concluded that these results established TAM receptors as both controllers of microglial physiology and potential targets for therapeutic intervention in CNS disease.
Using single-cell RNA sequencing in human and mouse non-small-cell lung cancers, Maier et al. (2020) identified a cluster of dendritic cells (DCs) that they named 'mature dendritic cells enriched in immunoregulatory molecules' (mregDCs), owing to their coexpression of immunoregulatory genes and maturation genes. Maier et al. (2020) found that the mregDC program is expressed by canonical DC1s and DC2s upon uptake of tumor antigens and further found that upregulation of PDL1 (605402), a key checkpoint molecule, in mregDCs is induced by the receptor tyrosine kinase AXL, while upregulation of interleukin-12 (IL12; see 161560) depends strictly on interferon-gamma (IFNG; 147570) and is controlled negatively by IL4 (147780) signaling. Blocking IL4 enhances IL12 production by tumor antigen-bearing mregDC1s, expands the pool of tumor-infiltrating effector T cells, and reduces tumor burden. Maier et al. (2020) concluded that they uncovered a regulatory module associated with tumor-antigen uptake that reduces DC1 functionality in human and mouse cancers.
By fluorescence in situ hybridization, O'Bryan et al. (1991) localized the AXL gene to 19q13.2.
By nonisotopic in situ hybridization, Janssen et al. (1991) mapped the AXL gene to 19q13.1.
Zhang et al. (2012) reported increased activation of AXL and evidence for epithelial-to-mesenchymal transition (EMT) in multiple in vitro and in vivo EGFR (131550)-mutant lung cancer models with acquired resistance to erlotinib in the absence of the EGFR T790M alteration (131550.0006) or MET activation. Genetic or pharmacologic inhibition of AXL restored sensitivity to erlotinib in these tumor models. Increased expression of AXL and, in some cases, of its ligand GAS6 (600441) was found in EGFR-mutant lung cancers obtained from individuals with acquired resistance to tyrosine kinase inhibitors.
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, and Tyro3 (600341). Like their ligands, GAS6 and PROS1 (176880), 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.
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]
Fourgeaud, L., Traves, P. G., Tufail, Y., Leal-Bailey, H., Lew, E. D., Burrola, P. G., Callaway, P., Zagorska, A., Rothlin, C. V., Nimmerjahn, A., Lemke, G. TAM receptors regulate multiple features of microglial physiology. Nature 532: 240-244, 2016. [PubMed: 27049947] [Full Text: https://doi.org/10.1038/nature17630]
Janssen, J. W. G., Schulz, A. S., Steenvoorden, A. C. M., Schmidberger, M., Strehl, S., Ambros, P. F., Bartram, C. R. A novel putative tyrosine kinase receptor with oncogenic potential. Oncogene 6: 2113-2120, 1991. [PubMed: 1834974]
Liu, E., Hjelle, B., Bishop, J. M. Transforming genes in chronic myelogenous leukemia. Proc. Nat. Acad. Sci. 85: 1952-1956, 1988. [PubMed: 3279421] [Full Text: https://doi.org/10.1073/pnas.85.6.1952]
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]
Maier, B., Leader, A. M., Chen, S. T., Tung, N., Chang, C., LeBerichel, J., Chudnovskiy, A., Maskey, S., Walker, L., Finnigan, J. P., Kirkling, M. E., Reizis, B., and 11 others. A conserved dendritic-cell regulatory program limits antitumour immunity. Nature 580: 257-262, 2020. Note: Erratum: Nature 582: E17, 2020. Electronic Article. [PubMed: 32269339] [Full Text: https://doi.org/10.1038/s41586-020-2134-y]
Manfioletti, G., Brancolini, C., Avanzi, G., Schneider, C. The protein encoded by a growth arrest-specific gene (gas6) is a new member of the vitamin K-dependent proteins related to protein S, a negative coregulator in the blood coagulation cascade. Molec. Cell. Biol. 13: 4976-4985, 1993. [PubMed: 8336730] [Full Text: https://doi.org/10.1128/mcb.13.8.4976-4985.1993]
Morizono, K., Xie, Y., Olafsen, T., Lee, B., Dasgupta, A., Wu, A. M., Chen, I. S. Y. The soluble serum protein Gas6 bridges virion envelope phosphatidylserine to the TAM receptor tyrosine kinase Axl to mediate viral entry. Cell Host Microbe 9: 286-298, 2011. [PubMed: 21501828] [Full Text: https://doi.org/10.1016/j.chom.2011.03.012]
O'Bryan, J. P., Frye, R. A., Cogswell, P. C., Neubauer, A., Kitch, B., Prokop, C., Espinosa, R., III, Le Beau, M. M., Earp, H. S., Liu, E. T. Axl, a transforming gene isolated from primary human myeloid leukemia cells, encodes a novel receptor tyrosine kinase. Molec. Cell. Biol. 11: 5016-5031, 1991. [PubMed: 1656220] [Full Text: https://doi.org/10.1128/mcb.11.10.5016-5031.1991]
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]
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]
Temperton, N. J., Wright, E. Retroviral pseudotypes. In: Encyclopedia of Life Sciences. Chichester, England: John Wiley & Sons, Ltd. 2009.
Varnum, B. C., Young, C., Elliott, G., Garcia, A., Bartley, T. D., Fridell, Y.-W., Hunt, R. W., Trail, G., Clogston, C., Toso, R. J., Yanagihara, D., Bennett, L., Sylber, M., Merewether, L. A., Tseng, A., Escobar, E., Liu, E. T., Yamane, H. K. Axl receptor tyrosine kinase stimulated by the vitamin K-dependent protein encoded by growth-arrest-specific gene 6. Nature 373: 623-626, 1995. [PubMed: 7854420] [Full Text: https://doi.org/10.1038/373623a0]
Zhang, Z., Lee, J. C., Lin, L., Olivas, V., Au, V., LaFramboise, T., Abdel-Rahman, M., Wang, X., Levine, A. D., Rho, J. K., Choi, Y. J., Choi, C.-M., and 18 others. Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. Nature Genet. 44: 852-860, 2012. [PubMed: 22751098] [Full Text: https://doi.org/10.1038/ng.2330]