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AXL

  • Living reference work entry
  • First Online:
Encyclopedia of Signaling Molecules

  • 61 Accesses

Synonyms

Adhesion-Related Kinase; ARK; AXL Receptor Tyrosine Kinase; JTK11; Tyro7; UFO

Historical Background

AXL, the founding member of the TAM (TYRO3, AXL, and MER) family of receptor tyrosine kinases, was concurrently discovered and characterized by multiple groups in 1991. In their seminal paper, O’Bryan and collaborators were able to transform fibroblasts transfected with DNA isolated from chronic myelogenous leukemic (CML) cells, subsequently isolating a novel transforming gene, which they named AXL based on the Greek word anexelekto, meaning uncontrolled (O’Bryan et al. 1991). Functional characterization of the product of this gene revealed a protein endowed with tyrosine kinase activity and a hydrophobic transmembrane domain which exhibited significant homology with numerous receptor tyrosine kinases (RTKs). Highlighting the oncogenic nature of this protein, they demonstrated that overexpression of AXLwas capable of inducing neoplastic transformation of fibroblasts. In a...

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References

  • Allen MP, Linseman DA, Udo H, Xu M, Schaack JB, Varnum B, et al. Novel mechanism for gonadotropin-releasing hormone neuronal migration involving GAS6/Ark signaling to p38 mitogen-activated protein kinase. Mol Cell Biol. 2002;22:599–613.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Allison AC. The possible role of vitamin K deficiency in the pathogenesis of Alzheimer’s disease and in augmenting brain damage associated with cardiovascular disease. Med Hypotheses. 2001;57:151–5. doi:10.1054/mehy.2001.1307.

    Article  CAS  PubMed  Google Scholar 

  • Asiedu MK, Beauchamp-Perez FD, Ingle JN, Behrens MD, Radisky DC, Knutson KL. AXL induces epithelial-to-mesenchymal transition and regulates the function of breast cancer stem cells. Oncogene. 2014;33:1316–24. doi:10.1038/onc.2013.57.

    Article  CAS  PubMed  Google Scholar 

  • Axelrod H, Pienta KJ. AXL as a mediator of cellular growth and survival. Oncotarget. 2014;5:8818–52. doi:10.18632/oncotarget.2422.

    Article  PubMed  PubMed Central  Google Scholar 

  • Barcena C, Stefanovic M, Tutusaus A, Joannas L, Menendez A, Garcia-Ruiz C, et al. AXL/gas6 pathway is activated in chronic liver disease and its targeting reduces fibrosis via hepatic stellate cell inactivation. J Hepatol. 2015;63:670–8. doi:10.1016/j.jhep.2015.04.013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brown M, Black JR, Sharma R, Stebbing J, Pinato DJ. Gene of the month: AXL. J Clin Pathol. 2016;69:391–7. doi:10.1136/jclinpath-2016-203629.

    Article  CAS  PubMed  Google Scholar 

  • Budagian V, Bulanova E, Orinska Z, Duitman E, Brandt K, Ludwig A, et al. Soluble AXL is generated by ADAM10-dependent cleavage and associates with GAS6 in mouse serum. Mol Cell Biol. 2005;25:9324–39. doi:10.1128/MCB.25.21.9324-9339.2005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ekman C, Jonsen A, Sturfelt G, Bengtsson AA, Dahlback B. Plasma concentrations of GAS6 and sAXL correlate with disease activity in systemic lupus erythematosus. Rheumatology (Oxford). 2011;50:1064–9. doi:10.1093/rheumatology/keq459.

    Article  CAS  Google Scholar 

  • Fourgeaud L, Traves PG, Tufail Y, Leal-Bailey H, Lew ED, Burrola PG, et al. TAM receptors regulate multiple features of microglial physiology. Nature. 2016;532:240–4. doi:10.1038/nature17630.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hafizi S, Alindri F, Karlsson R, Dahlback B. Interaction of AXL receptor tyrosine kinase with C1-TEN, a novel C1 domain-containing protein with homology to tensin. Biochem Biophys Res Commun. 2002;299:793–800.

    Article  CAS  PubMed  Google Scholar 

  • Han J, Bae J, Choi CY, Choi SP, Kang HS, Jo EK, et al. Autophagy induced by AXL receptor tyrosine kinase alleviates acute liver injury via inhibition of NLRP3 inflammasome activation in mice. Autophagy. 2016. doi:10.1080/15548627.2016.1235124.

    Google Scholar 

  • Huang M, Rigby AC, Morelli X, Grant MA, Huang G, Furie B, et al. Structural basis of membrane binding by Gla domains of vitamin K-dependent proteins. Nat Struct Biol. 2003;10:751–6. doi:10.1038/nsb971.

    Article  CAS  PubMed  Google Scholar 

  • Janssen JW, Schulz AS, Steenvoorden AC, Schmidberger M, Strehl S, Ambros PF, et al. A novel putative tyrosine kinase receptor with oncogenic potential. Oncogene. 1991;6:2113–20.

    CAS  PubMed  Google Scholar 

  • Kawasaki Y, Nakagawa A, Nagaosa K, Shiratsuchi A, Nakanishi Y. Phosphatidylserine binding of class B scavenger receptor type I, a phagocytosis receptor of testicular sertoli cells. J Biol Chem. 2002;277:27559–66. doi:10.1074/jbc.M202879200.

    Article  CAS  PubMed  Google Scholar 

  • Kim EM, Lee EH, Lee HY, Choi HR, Ji KY, Kim SM, et al. AXL signaling induces development of natural killer cells in vitro and in vivo. Protoplasma. 2016. doi:10.1007/s00709-016-1016-5.

    PubMed Central  Google Scholar 

  • Korshunov VA. AXL-dependent signalling: a clinical update. Clin Sci (Lond). 2012;122:361–8. doi:10.1042/CS20110411.

    Article  CAS  Google Scholar 

  • Lai C, Lemke G. An extended family of protein-tyrosine kinase genes differentially expressed in the vertebrate nervous system. Neuron. 1991;6:691–704.

    Article  CAS  PubMed  Google Scholar 

  • Lemke G. Biology of the TAM receptors. Cold Spring Harb Perspect Biol. 2013;5:a009076. doi:10.1101/cshperspect.a009076.

    Article  PubMed  PubMed Central  Google Scholar 

  • Lemke G, Rothlin CV. Immunobiology of the TAM receptors. Nat Rev Immunol. 2008;8:327–36. doi:10.1038/nri2303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Linger RM, Keating AK, Earp HS, Graham DK. TAM receptor tyrosine kinases: biologic functions, signaling, and potential therapeutic targeting in human cancer. Adv Cancer Res. 2008;100:35–83. doi:10.1016/S0065-230X(08)00002-X.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu S, DeLalio LJ, Isakson BE, Wang TT. AXL-mediated productive infection of human endothelial cells by Zika virus. Circ Res. 2016. doi:10.1161/CIRCRESAHA.116.309866.

    Google Scholar 

  • Lu Q, Gore M, Zhang Q, Camenisch T, Boast S, Casagranda F, et al. Tyro-3 family receptors are essential regulators of mammalian spermatogenesis. Nature. 1999;398:723–8. doi:10.1038/19554.

    Article  CAS  PubMed  Google Scholar 

  • 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. Mol Cell Biol. 1993;13:4976–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mark MR, Chen J, Hammonds RG, Sadick M, Godowsk PJ. Characterization of GAS6, a member of the superfamily of G domain-containing proteins, as a ligand for Rse and AXL. J Biol Chem. 1996;271:9785–9.

    Article  CAS  PubMed  Google Scholar 

  • Melaragno MG, Cavet ME, Yan C, Tai LK, Jin ZG, Haendeler J, et al. GAS6 inhibits apoptosis in vascular smooth muscle: role of AXL kinase and Akt. J Mol Cell Cardiol. 2004;37:881–7. doi:10.1016/j.yjmcc.2004.06.018.

    Article  CAS  PubMed  Google Scholar 

  • Mok CC, Ding HH, Kharboutli M, Mohan C. AXL, ferritin, insulin-like growth factor binding protein 2, and tumor necrosis factor receptor type II as biomarkers in systemic lupus erythematosus. Arthritis Care Res (Hoboken). 2016;68:1303–9. doi:10.1002/acr.22835.

    Article  CAS  Google Scholar 

  • Mudduluru G, Allgayer H. The human receptor tyrosine kinase AXL gene – promoter characterization and regulation of constitutive expression by Sp1, Sp3 and CpG methylation. Biosci Rep. 2008;28:161–76. doi:10.1042/BSR20080046.

    CAS  PubMed  Google Scholar 

  • Mudduluru G, Ceppi P, Kumarswamy R, Scagliotti GV, Papotti M, Allgayer H. Regulation of AXL receptor tyrosine kinase expression by miR-34a and miR-199a/b in solid cancer. Oncogene. 2011;30:2888–99. doi:10.1038/onc.2011.13.

    Article  CAS  PubMed  Google Scholar 

  • Nowakowski TJ, Pollen AA, Di Lullo E, Sandoval-Espinosa C, Bershteyn M, Kriegstein AR. Expression analysis highlights AXL as a candidate Zika virus entry receptor in neural stem cells. Cell Stem Cell. 2016;18:591–6. doi:10.1016/j.stem.2016.03.012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • O’Bryan JP, Frye RA, Cogswell PC, Neubauer A, Kitch B, Prokop C, et al. AXL, a transforming gene isolated from primary human myeloid leukemia cells, encodes a novel receptor tyrosine kinase. Mol Cell Biol. 1991;11:5016–31.

    Article  PubMed  PubMed Central  Google Scholar 

  • Paccez JD, Vogelsang M, Parker MI, Zerbini LF. The receptor tyrosine kinase AXL in cancer: biological functions and therapeutic implications. Int J Cancer. 2014;134:1024–33. doi:10.1002/ijc.28246.

    Article  CAS  PubMed  Google Scholar 

  • Paolino M, Penninger JM. The role of TAM family receptors in immune cell function: implications for cancer therapy. Cancers (Basel). 2016;8. doi:10.3390/cancers8100097.

    Google Scholar 

  • Park IK, Trotta R, Yu J, Caligiuri MA. AXL/GAS6 pathway positively regulates FLT3 activation in human natural killer cell development. Eur J Immunol. 2013;43:2750–5. doi:10.1002/eji.201243116.

    Article  CAS  PubMed  Google Scholar 

  • Rescigno J, Mansukhani A, Basilico C. A putative receptor tyrosine kinase with unique structural topology. Oncogene. 1991;6:1909–13.

    CAS  PubMed  Google Scholar 

  • Sasaki T, Knyazev PG, Clout NJ, Cheburkin Y, Gohring W, Ullrich A, et al. Structural basis for GAS6-AXL signalling. EMBO J. 2006;25:80–7. doi:10.1038/sj.emboj.7600912.

    Article  CAS  PubMed  Google Scholar 

  • Savage JC, Jay T, Goduni E, Quigley C, Mariani MM, Malm T, et al. Nuclear receptors license phagocytosis by trem2+ myeloid cells in mouse models of Alzheimer’s disease. J Neurosci. 2015;35:6532–43. doi:10.1523/JNEUROSCI.4586-14.2015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schulz AS, Schleithoff L, Faust M, Bartram CR, Janssen JW. The genomic structure of the human UFO receptor. Oncogene. 1993;8:509–13.

    CAS  PubMed  Google Scholar 

  • Suh CH, Hilliard B, Li S, MERrill JT, Cohen PL. TAM receptor ligands in lupus: protein S but not GAS6 levels reflect disease activity in systemic lupus erythematosus. Arthritis Res Ther. 2010;12:R146. doi:10.1186/ar3088.

    Article  PubMed  PubMed Central  Google Scholar 

  • Tai KY, Shieh YS, Lee CS, Shiah SG, Wu CW. AXL promotes cell invasion by inducing MMP-9 activity through activation of NF-kappaB and Brg-1. Oncogene. 2008;27:4044–55. doi:10.1038/onc.2008.57.

    Article  CAS  PubMed  Google Scholar 

  • Valverde P. Effects of GAS6 and hydrogen peroxide in AXL ubiquitination and downregulation. Biochem Biophys Res Commun. 2005;333:180–5. doi:10.1016/j.bbrc.2005.05.086.

    Article  CAS  PubMed  Google Scholar 

  • Vouri M, Croucher DR, Kennedy SP, An Q, Pilkington GJ, Hafizi S. AXL-EGFR receptor tyrosine kinase hetero-interaction provides EGFR with access to pro-invasive signalling in cancer cells. Oncogenesis. 2016;5:e266. doi:10.1038/oncsis.2016.66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu X, Liu X, Koul S, Lee CY, Zhang Z, Halmos B. AXL kinase as a novel target for cancer therapy. Oncotarget. 2014;5:9546–63. doi:10.18632/oncotarget.2542.

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhang Z, Lee JC, Lin L, Olivas V, Au V, LaFramboise T, et al. Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. Nat Genet. 2012;44:852–60. doi:10.1038/ng.2330.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou L, Liu XD, Sun M, Zhang X, German P, Bai S, et al. Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma. Oncogene. 2016;35:2687–97. doi:10.1038/onc.2015.343.

    Article  CAS  PubMed  Google Scholar 

  • Zhu H, Sun X, Zhu L, Hu F, Shi L, Fan C, et al. Different expression patterns and clinical significance of mAXL and sAXL in systemic lupus erythematosus. Lupus. 2014;23:624–34. doi:10.1177/0961203314520839.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London, W12 0HS, UK

    Matthew W Brown & David J Pinato

Authors
  1. Matthew W Brown
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  2. David J Pinato
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Correspondence to David J Pinato .

Editor information

Editors and Affiliations

  1. Dept. Biological Science, Department of Molecular Science and Tech College of Natural Science, Suwon, Korea (Republic of)

    Sangdun Choi

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Brown, M.W., Pinato, D.J. (2016). AXL. In: Choi, S. (eds) Encyclopedia of Signaling Molecules. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-6438-9_101916-1

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  • DOI: https://doi.org/10.1007/978-1-4614-6438-9_101916-1

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  • Print ISBN: 978-1-4614-6438-9

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