Skip to main content

Axl and Mer Receptor Tyrosine Kinases: Distinct and Nonoverlapping Roles in Inflammation and Cancer?

  • Chapter
  • First Online:
Apoptosis in Cancer Pathogenesis and Anti-cancer Therapy

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 930))

Abstract

The receptor tyrosine kinases Axl and Mer subserve the process of termination of proinflammatory signaling and have key roles in both the resolution of inflammation and restoration of homeostasis. Axl functions prominently under conditions of tissue stress or in response to infection, whereas Mer has a major role in maintenance of homeostasis within tissues. Distinct patterns of expression of Axl and Mer underlie their clearly defined functional roles during the initiation and progression of inflammation. Axl and Mer are expressed by tumor cells and by infiltrating inflammatory cells and the regulation of cellular function via Axl and Mer signaling is also important for tumorigenesis, tumor progression, and metastasis. In this review, we consider the divergent functions of Axl and Mer in the context of inflammatory processes within tumors and the implications for development of therapeutic agents targeting these receptors.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Chovatiya R, Medzhitov R. Stress, inflammation, and defense of homeostasis. Mol Cell. 2014;54:281–8. doi:10.1016/j.molcel.2014.03.030.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Balkwill FR, Mantovani A. Cancer-related inflammation: common themes and therapeutic opportunities. Semin Cancer Biol. 2012;22:33–40. doi:10.1016/j.semcancer.2011.12.005.

    Article  CAS  PubMed  Google Scholar 

  3. Nathan C. Points of control in inflammation. Nature. 2002;420:846–52. doi:10.1038/nature01320.

    Article  CAS  PubMed  Google Scholar 

  4. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454:436–44. doi:10.1038/nature07205.

    Article  CAS  PubMed  Google Scholar 

  5. 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 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bhattacharyya S, Zagórska A, Lew ED, et al. Enveloped viruses disable innate immune responses in dendritic cells by direct activation of TAM receptors. Cell Host Microbe. 2013;14:136–47. doi:10.1016/j.chom.2013.07.005.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Rothlin CV, Ghosh S, Zuniga EI, et al. TAM receptors are pleiotropic inhibitors of the innate immune response. Cell. 2007;131:1124–36. doi:10.1016/j.cell.2007.10.034.

    Article  CAS  PubMed  Google Scholar 

  9. Zagórska A, Través PG, Lew ED, et al. Diversification of TAM receptor tyrosine kinase function. Nat Immunol. 2014. doi:10.1038/ni.2986.

    PubMed  PubMed Central  Google Scholar 

  10. 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 

  11. O’Bryan JP, Frye RA, Cogswell PC, 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 

  12. Graham DK, Dawson T, Mullaney D, et al. Cloning and mRNA expression analysis of a novel human protooncogene, c-mer. 1994;5:647–57.

    Google Scholar 

  13. Camenisch TD, Koller BH, Earp HS, Matsushima GK. A novel receptor tyrosine kinase, Mer, inhibits TNF-alpha production and lipopolysaccharide-induced endotoxic shock. J Immunol. 1999;162:3498–503.

    CAS  PubMed  Google Scholar 

  14. Lu Q, Gore M, Zhang Q, 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 

  15. Lu Q, Lemke G. Homeostatic regulation of the immune system by receptor tyrosine kinases of the Tyro 3 family. Science. 2001;293:306–11. doi:10.1126/science.1061663.

    Article  CAS  PubMed  Google Scholar 

  16. Stitt TN, Conn G, Gore M, et al. The anticoagulation factor protein S and its relative, Gas6, are ligands for the Tyro 3/Axl family of receptor tyrosine kinases. Cell. 1995;80:661–70.

    Article  CAS  PubMed  Google Scholar 

  17. Di Scipio RG, Hermodson MA, Yates SG, Davie EW. A comparison of human prothrombin, factor IX (Christmas factor), factor X (Stuart factor), and protein S. Biochemistry (Mosc). 1977;16:698–706.

    Article  Google Scholar 

  18. 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 

  19. Lew ED, Oh J, Burrola PG, et al. Differential TAM receptor-ligand-phospholipid interactions delimit differential TAM bioactivities. eLife. 2014. doi:10.7554/eLife.03385.

    PubMed  PubMed Central  Google Scholar 

  20. Dransfield I, Zagórska A, Lew ED, et al. Mer receptor tyrosine kinase mediates both tethering and phagocytosis of apoptotic cells. Cell Death Dis. 2015;6, e1646. doi:10.1038/cddis.2015.18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. O’Bryan JP, Fridell YW, Koski R, et al. The transforming receptor tyrosine kinase, Axl, is post-translationally regulated by proteolytic cleavage. J Biol Chem. 1995;270:551–7.

    Article  PubMed  Google Scholar 

  22. Sather S, Kenyon KD, Lefkowitz JB, et al. A soluble form of the Mer receptor tyrosine kinase inhibits macrophage clearance of apoptotic cells and platelet aggregation. Blood. 2007;109:1026–33. doi:10.1182/blood-2006-05-021634.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lee IJ, Hilliard BA, Ulas M, et al. Monocyte and plasma expression of TAM ligand and receptor in renal failure: Links to unregulated immunity and chronic inflammation. Clin Immunol. 2015;158:231–41. doi:10.1016/j.clim.2015.01.012.

    Article  CAS  PubMed  Google Scholar 

  24. Weinger JG, Omari KM, Marsden K, et al. Up-regulation of soluble Axl and Mer receptor tyrosine kinases negatively correlates with Gas6 in established multiple sclerosis lesions. Am J Pathol. 2009;175:283–93. doi:10.2353/ajpath.2009.080807.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ko C-P, Yu Y-L, Hsiao P-C, et al. Plasma levels of soluble Axl correlate with severity of community-acquired pneumonia. Mol Med Rep. 2014;9:1400–4. doi:10.3892/mmr.2014.1933.

    CAS  PubMed  Google Scholar 

  26. Ekman C, Gottsäter A, Lindblad B, Dahlbäck B. Plasma concentrations of Gas6 and soluble Axl correlate with disease and predict mortality in patients with critical limb ischemia. Clin Biochem. 2010;43:873–6. doi:10.1016/j.clinbiochem.2010.04.006.

    Article  CAS  PubMed  Google Scholar 

  27. Zhu H, Sun X, Zhu L, et al. Different expression patterns and clinical significance of mAxl and sAxl in systemic lupus erythematosus. Lupus. 2014. doi:10.1177/0961203314520839.

    Google Scholar 

  28. Hsiao F-C, Lin Y-F, Hsieh P-S, et al. Circulating growth arrest-specific 6 protein is associated with adiposity, systemic inflammation, and insulin resistance among overweight and obese adolescents. J Clin Endocrinol Metab. 2013;98:E267–74. doi:10.1210/jc.2012-3179.

    Article  CAS  PubMed  Google Scholar 

  29. Liu X, Gong Y, Jia J, et al. Plasma concentrations of sAxl are associated with severe preeclampsia. Clin Biochem. 2014;47:173–6. doi:10.1016/j.clinbiochem.2013.11.001.

    Article  CAS  PubMed  Google Scholar 

  30. Liu Y-W, Yang Q-F, Zuo P-Y, et al. Elevated serum levels of soluble Axl in acute coronary syndrome. Am J Med Sci. 2015;349:124–9. doi:10.1097/MAJ.0000000000000362.

    Article  PubMed  Google Scholar 

  31. Ekman C, Site DF, Gottsäter A, et al. Plasma concentrations of growth arrest specific protein 6 and the soluble form of its tyrosine kinase receptor Axl as markers of large abdominal aortic aneurysms. Clin Biochem. 2010;43:110–4. doi:10.1016/j.clinbiochem.2009.07.025.

    Article  CAS  PubMed  Google Scholar 

  32. Xu J, Ma F, Yan W, et al. Identification of the soluble form of tyrosine kinase receptor Axl as a potential biomarker for intracranial aneurysm rupture. BMC Neurol. 2015;15:23. doi:10.1186/s12883-015-0282-8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Qin B, Wang J, Ma N, et al. The association of Tyro3/Axl/Mer signaling with inflammatory response, disease activity in patients with primary Sjögren’s syndrome. Joint Bone Spine. 2015. doi:10.1016/j.jbspin.2015.01.008.

    PubMed  Google Scholar 

  34. Ballantine L, Midgley A, Harris D, et al. Increased soluble phagocytic receptors sMer, sTyro3 and sAxl and reduced phagocytosis in juvenile-onset systemic lupus erythematosus. Pediatr Rheumatol Online J. 2015;13:10. doi:10.1186/s12969-015-0007-y.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Costa M, Bellosta P, Basilico C. Cleavage and release of a soluble form of the receptor tyrosine kinase ARK in vitro and in vivo. J Cell Physiol. 1996;168:737–44. doi:10.1002/(SICI)1097-4652(199609)168:3<737::AID-JCP27>3.0.CO;2-U.

    Article  CAS  PubMed  Google Scholar 

  36. Gustafsson A, Martuszewska D, Johansson M, et al. Differential expression of Axl and Gas6 in renal cell carcinoma reflecting tumor advancement and survival. Clin Cancer Res. 2009;15:4742–9. doi:10.1158/1078-0432.CCR-08-2514.

    Article  CAS  PubMed  Google Scholar 

  37. Reichl P, Fang M, Starlinger P, et al. Multicenter analysis of soluble Axl reveals diagnostic value for very early stage hepatocellular carcinoma. Int J Cancer. 2015;137:385–94. doi:10.1002/ijc.29394.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Johansson G, Peng P-C, Huang P-Y, et al. Soluble AXL: a possible circulating biomarker for neurofibromatosis type 1 related tumor burden. PLoS One. 2014;9, e115916. doi:10.1371/journal.pone.0115916.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Fadok VA, Bratton DL, Konowal A, et al. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J Clin Invest. 1998;101:890–8. doi:10.1172/JCI1112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Voll RE, Herrmann M, Roth EA, et al. Immunosuppressive effects of apoptotic cells. Nature. 1997;390:350–1. doi:10.1038/37022.

    Article  CAS  PubMed  Google Scholar 

  41. Hochreiter-Hufford A, Ravichandran KS. Clearing the dead: apoptotic cell sensing, recognition, engulfment, and digestion. Cold Spring Harb Perspect Biol. 2013;5:a008748. doi:10.1101/cshperspect.a008748.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Savill J, Dransfield I, Gregory C, Haslett C. A blast from the past: clearance of apoptotic cells regulates immune responses. Nat Rev Immunol. 2002;2:965–75. doi:10.1038/nri957.

    Article  CAS  PubMed  Google Scholar 

  43. Gautier EL, Shay T, Miller J, et al. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat Immunol. 2012;13:1118–28. doi:10.1038/ni.2419.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Gal A, Li Y, Thompson DA, et al. Mutations in MERTK, the human orthologue of the RCS rat retinal dystrophy gene, cause retinitis pigmentosa. Nat Genet. 2000;26:270–1. doi:10.1038/81555.

    Article  CAS  PubMed  Google Scholar 

  45. Rahman ZSM, Shao W-H, Khan TN, et al. Impaired apoptotic cell clearance in the germinal center by Mer-deficient tingible body macrophages leads to enhanced antibody-forming cell and germinal center responses. J Immunol. 2010;185:5859–68. doi:10.4049/jimmunol.1001187.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Casanova-Acebes M, Pitaval C, Weiss LA, et al. Rhythmic modulation of the hematopoietic niche through neutrophil clearance. Cell. 2013;153:1025–35. doi:10.1016/j.cell.2013.04.040.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Irschick EU, Haas G, Geiger M, et al. Phagocytosis of human retinal pigment epithelial cells: evidence of a diurnal rhythm, involvement of the cytoskeleton and interference of antiviral drugs. Ophthalmic Res. 2006;38:164–74. doi:10.1159/000091476.

    Article  CAS  PubMed  Google Scholar 

  48. Bauer T, Zagórska A, Jurkin J, et al. Identification of Axl as a downstream effector of TGF-β1 during Langerhans cell differentiation and epidermal homeostasis. J Exp Med. 2012;209:2033–47. doi:10.1084/jem.20120493.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Fujimori T, Grabiec AM, Kaur M, et al. The Axl receptor tyrosine kinase is a discriminator of macrophage function in the inflamed lung. Mucosal Immunol. 2015;8:1021–30. doi:10.1038/mi.2014.129.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Graham DK, Deryckere D, Davies KD, Earp HS. The TAM family: phosphatidylserine sensing receptor tyrosine kinases gone awry in cancer. Nat Publ Group. 2014;14:769–85. doi: 10.1038/nrc3847.

    Google Scholar 

  51. Rochlitz C, Lohri A, Bacchi M, et al. Axl expression is associated with adverse prognosis and with expression of Bcl-2 and CD34 in de novo acute myeloid leukemia (AML): results from a multicenter trial of the Swiss Group for Clinical Cancer Research (SAKK). Leukemia. 1999;13:1352–8.

    Article  CAS  PubMed  Google Scholar 

  52. Ghosh AK, Secreto C, Boysen J, et al. The novel receptor tyrosine kinase Axl is constitutively active in B-cell chronic lymphocytic leukemia and acts as a docking site of nonreceptor kinases: implications for therapy. Blood. 2011;117:1928–37. doi:10.1182/blood-2010-09-305649.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Neubauer A, Fiebeler A, Graham DK, et al. Expression of axl, a transforming receptor tyrosine kinase, in normal and malignant hematopoiesis. Blood. 1994;84:1931–41.

    CAS  PubMed  Google Scholar 

  54. Graham DK, Salzberg DB, Kurtzberg J, et al. Ectopic expression of the proto-oncogene Mer in pediatric T-cell acute lymphoblastic leukemia. Clin Cancer Res. 2006;12:2662–9. doi:10.1158/1078-0432.CCR-05-2208.

    Article  CAS  PubMed  Google Scholar 

  55. Brandao LN, Winges A, Christoph S, et al. Inhibition of MerTK increases chemosensitivity and decreases oncogenic potential in T-cell acute lymphoblastic leukemia. Blood Cancer J. 2013;3, e101. doi:10.1038/bcj.2012.46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Lee-Sherick AB, Eisenman KM, Sather S, et al. Aberrant Mer receptor tyrosine kinase expression contributes to leukemogenesis in acute myeloid leukemia. Oncogene. 2013;32:5359–68. doi:10.1038/onc.2013.40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Ek S, Högerkorp C-M, Dictor M, et al. Mantle cell lymphomas express a distinct genetic signature affecting lymphocyte trafficking and growth regulation as compared with subpopulations of normal human B cells. Cancer Res. 2002;62:4398–405.

    CAS  PubMed  Google Scholar 

  58. Evans CO, Young AN, Brown MR, et al. Novel patterns of gene expression in pituitary adenomas identified by complementary deoxyribonucleic acid microarrays and quantitative reverse transcription-polymerase chain reaction. J Clin Endocrinol Metab. 2001;86:3097–107. doi:10.1210/jcem.86.7.7616.

    CAS  PubMed  Google Scholar 

  59. Wu Y-M, Robinson DR, Kung H-J. Signal pathways in up-regulation of chemokines by tyrosine kinase MER/NYK in prostate cancer cells. Cancer Res. 2004;64:7311–20. doi:10.1158/0008-5472.CAN-04-0972.

    Article  CAS  PubMed  Google Scholar 

  60. Schlegel J, Sambade MJ, Sather S, et al. MERTK receptor tyrosine kinase is a therapeutic target in melanoma. J Clin Invest. 2013;123:2257–67. doi:10.1172/JCI67816.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Tworkoski KA, Platt JT, Bacchiocchi A, et al. MERTK controls melanoma cell migration and survival and differentially regulates cell behavior relative to AXL. Pigment Cell Melanoma Res. 2013;26:527–41. doi:10.1111/pcmr.12110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Reinartz S, Schumann T, Finkernagel F, et al. Mixed-polarization phenotype of ascites-associated macrophages in human ovarian carcinoma: correlation of CD163 expression, cytokine levels and early relapse. Int J Cancer. 2014;134:32–42. doi:10.1002/ijc.28335.

    Article  PubMed  CAS  Google Scholar 

  63. Ryder M, Ghossein RA, Ricarte-Filho JCM, et al. Increased density of tumor-associated macrophages is associated with decreased survival in advanced thyroid cancer. Endocr Relat Cancer. 2008;15:1069–74. doi:10.1677/ERC-08-0036.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Zhu X-D, Zhang J-B, Zhuang P-Y, et al. High expression of macrophage colony-stimulating factor in peritumoral liver tissue is associated with poor survival after curative resection of hepatocellular carcinoma. J Clin Oncol. 2008;26:2707–16. doi:10.1200/JCO.2007.15.6521.

    Article  PubMed  Google Scholar 

  65. Gazzaniga S, Bravo AI, Guglielmotti A, et al. Targeting tumor-associated macrophages and inhibition of MCP-1 reduce angiogenesis and tumor growth in a human melanoma xenograft. J Invest Dermatol. 2007;127:2031–41. doi:10.1038/sj.jid.5700827.

    Article  CAS  PubMed  Google Scholar 

  66. Kimura YN, Watari K, Fotovati A, et al. Inflammatory stimuli from macrophages and cancer cells synergistically promote tumor growth and angiogenesis. Cancer Sci. 2007;98:2009–18. doi:10.1111/j.1349-7006.2007.00633.x.

    Article  CAS  PubMed  Google Scholar 

  67. Zeisberger SM, Odermatt B, Marty C, et al. Clodronate-liposome-mediated depletion of tumor-associated macrophages: a new and highly effective antiangiogenic therapy approach. Br J Cancer. 2006;95:272–81. doi:10.1038/sj.bjc.6603240.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Qian B-Z, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell. 2010;141:39–51. doi:10.1016/j.cell.2010.03.014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Heuff G, Oldenburg HS, Boutkan H, et al. Enhanced tumor growth in the rat liver after selective elimination of Kupffer cells. Cancer Immunol Immunother. 1993;37:125–30.

    Article  CAS  PubMed  Google Scholar 

  70. Franklin RA, Liao W, Sarkar A, et al. The cellular and molecular origin of tumor-associated macrophages. Science. 2014;344:921–5. doi:10.1126/science.1252510.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Shand FHW, Ueha S, Otsuji M, et al. Tracking of intertissue migration reveals the origins of tumor-infiltrating monocytes. Proc Natl Acad Sci U S A. 2014;111:7771–6. doi:10.1073/pnas.1402914111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Bonavita E, Gentile S, Rubino M, et al. PTX3 is an extrinsic oncosuppressor regulating complement-dependent inflammation in cancer. Cell. 2015;160:700–14. doi:10.1016/j.cell.2015.01.004.

    Article  CAS  PubMed  Google Scholar 

  73. Tripathi C, Tewari BN, Kanchan RK, et al. Macrophages are recruited to hypoxic tumor areas and acquire a pro-angiogenic M2-polarized phenotype via hypoxic cancer cell derived cytokines Oncostatin M and Eotaxin. Oncotarget. 2014;5:5350–68.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Bottazzi B, Erba E, Nobili N, et al. A paracrine circuit in the regulation of the proliferation of macrophages infiltrating murine sarcomas. J Immunol. 1990;144:2409–12.

    CAS  PubMed  Google Scholar 

  75. Mantovani A, Biswas SK, Galdiero MR, et al. Macrophage plasticity and polarization in tissue repair and remodelling. J Pathol. 2013;229:176–85. doi:10.1002/path.4133.

    Article  CAS  PubMed  Google Scholar 

  76. Mantovani A, Germano G, Marchesi F, et al. Cancer-promoting tumor-associated macrophages: new vistas and open questions. Eur J Immunol. 2011;41:2522–5. doi:10.1002/eji.201141894.

    Article  CAS  PubMed  Google Scholar 

  77. Movahedi K, Laoui D, Gysemans C, et al. Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes. Cancer Res. 2010;70:5728–39. doi:10.1158/0008-5472.CAN-09-4672.

    Article  CAS  PubMed  Google Scholar 

  78. Zizzo G, Hilliard BA, Monestier M, Cohen PL. Efficient clearance of early apoptotic cells by human macrophages requires M2c polarization and MerTK induction. J Immunol. 2012;189:3508–20. doi:10.4049/jimmunol.1200662.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Chiang C-S, Fu SY, Wang S-C, et al. Irradiation promotes an m2 macrophage phenotype in tumor hypoxia. Front Oncol. 2012;2:89. doi:10.3389/fonc.2012.00089.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Leek RD, Talks KL, Pezzella F, et al. Relation of hypoxia-inducible factor-2 alpha (HIF-2 alpha) expression in tumor-infiltrative macrophages to tumor angiogenesis and the oxidative thymidine phosphorylase pathway in Human breast cancer. Cancer Res. 2002;62:1326–9.

    CAS  PubMed  Google Scholar 

  81. Negus RP, Turner L, Burke F, Balkwill FR. Hypoxia down-regulates MCP-1 expression: implications for macrophage distribution in tumors. J Leukoc Biol. 1998;63:758–65.

    CAS  PubMed  Google Scholar 

  82. Chittezhath M, Dhillon MK, Lim JY, et al. Molecular profiling reveals a tumor-promoting phenotype of monocytes and macrophages in human cancer progression. Immunity. 2014;41:815–29. doi:10.1016/j.immuni.2014.09.014.

    Article  CAS  PubMed  Google Scholar 

  83. Laoui D, Van Overmeire E, Di Conza G, et al. Tumor hypoxia does not drive differentiation of tumor-associated macrophages but rather fine-tunes the M2-like macrophage population. Cancer Res. 2014;74:24–30. doi:10.1158/0008-5472.CAN-13-1196.

    Article  CAS  PubMed  Google Scholar 

  84. Rankin EB, Fuh KC, Castellini L, et al. Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET. Proc Natl Acad Sci U S A. 2014;111:13373–8. doi:10.1073/pnas.1404848111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Mishra A, Wang J, Shiozawa Y, et al. Hypoxia stabilizes GAS6/Axl signaling in metastatic prostate cancer. Mol Cancer Res. 2012;10:703–12. doi:10.1158/1541-7786.MCR-11-0569.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Pierce A, Bliesner B, Xu M, et al. Axl and Tyro3 modulate female reproduction by influencing gonadotropin-releasing hormone neuron survival and migration. Mol Endocrinol. 2008;22:2481–95. doi:10.1210/me.2008-0169.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Tai K-Y, Shieh Y-S, Lee C-S, et al. 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 

  88. Huang J-S, Cho C-Y, Hong C-C, et al. Oxidative stress enhances Axl-mediated cell migration through an Akt1/Rac1-dependent mechanism. Free Radic Biol Med. 2013;65:1246–56. doi:10.1016/j.freeradbiomed.2013.09.011.

    Article  CAS  PubMed  Google Scholar 

  89. McIntyre A, Harris AL. Metabolic and hypoxic adaptation to anti-angiogenic therapy: a target for induced essentiality. EMBO Mol Med. 2015;7:368–79. doi:10.15252/emmm.201404271.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. A-Gonzalez N, Bensinger SJ, Hong C, et al. Apoptotic cells promote their own clearance and immune tolerance through activation of the nuclear receptor LXR. Immunity. 2009;31:245–58. doi:10.1016/j.immuni.2009.06.018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Hodrea J, Majai G, Doró Z, et al. The glucocorticoid dexamethasone programs human dendritic cells for enhanced phagocytosis of apoptotic neutrophils and inflammatory response. J Leukoc Biol. 2012;91:127–36. doi:10.1189/jlb.0511243.

    Article  CAS  PubMed  Google Scholar 

  92. McColl A, Michlewska S, Dransfield I, Rossi AG. Effects of glucocorticoids on apoptosis and clearance of apoptotic cells. ScientificWorldJournal. 2007;7:1165–81. doi:10.1100/tsw.2007.224.

    Article  CAS  PubMed  Google Scholar 

  93. Stanford JC, Young C, Hicks D, et al. Efferocytosis produces a prometastatic landscape during postpartum mammary gland involution. J Clin Invest. 2014;124:4737–52. doi:10.1172/JCI76375.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Ford CA, Petrova S, Pound JD, et al. Oncogenic properties of apoptotic tumor cells in aggressive B cell lymphoma. Curr Biol. 2015;25:577–88. doi:10.1016/j.cub.2014.12.059.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Sinha S, Boysen J, Nelson M, et al. Targeted Axl inhibition primes chronic lymphocytic leukemia B cells to apoptosis and shows synergistic/additive effects in combination with BTK inhibitors. Clin Cancer Res. 2015;21:2115–26. doi:10.1158/1078-0432.CCR-14-1892.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Hulsmans M, Holvoet P. MicroRNA-containing microvesicles regulating inflammation in association with atherosclerotic disease. Cardiovasc Res. 2013;100:7–18. doi:10.1093/cvr/cvt161.

    Article  CAS  PubMed  Google Scholar 

  97. Hong C-C, Lay J-D, Huang J-S, et al. Receptor tyrosine kinase AXL is induced by chemotherapy drugs and overexpression of AXL confers drug resistance in acute myeloid leukemia. Cancer Lett. 2008;268:314–24. doi:10.1016/j.canlet.2008.04.017.

    Article  CAS  PubMed  Google Scholar 

  98. Ammoun S, Provenzano L, Zhou L, et al. Axl/Gas6/NFkB signaling in Schwannoma pathological proliferation, adhesion and survival. Oncogene. 2014;33:336–46. doi:10.1038/onc.2012.587.

    Article  CAS  PubMed  Google Scholar 

  99. Zhang Y-X, Knyazev PG, Cheburkin YV, et al. AXL is a potential target for therapeutic intervention in breast cancer progression. Cancer Res. 2008;68:1905–15. doi:10.1158/0008-5472.CAN-07-2661.

    Article  CAS  PubMed  Google Scholar 

  100. Giles KM, Kalinowski FC, Candy PA, et al. Axl mediates acquired resistance of head and neck cancer cells to the epidermal growth factor receptor inhibitor erlotinib. Mol Cancer Ther. 2013;12:2541–58. doi:10.1158/1535-7163.MCT-13-0170.

    Article  CAS  PubMed  Google Scholar 

  101. Fleuren EDG, Hillebrandt-Roeffen MHS, Flucke UE, et al. The role of AXL and the in vitro activity of the receptor tyrosine kinase inhibitor BGB324 in Ewing sarcoma. Oncotarget. 2014;5:12753–68.

    Article  PubMed  PubMed Central  Google Scholar 

  102. Mahadevan D, Cooke L, Riley C, et al. A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors. Oncogene. 2007;26:3909–19. doi:10.1038/sj.onc.1210173.

    Article  CAS  PubMed  Google Scholar 

  103. Brand TM, Iida M, Stein AP, et al. AXL mediates resistance to cetuximab therapy. Cancer Res. 2014;74:5152–64. doi:10.1158/0008-5472.CAN-14-0294.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Zhang Z, Lee JC, Lin L, 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 

  105. Liu L, Greger J, Shi H, et al. Novel mechanism of lapatinib resistance in HER2-positive breast tumor cells: activation of AXL. Cancer Res. 2009;69:6871–8. doi:10.1158/0008-5472.CAN-08-4490.

    Article  CAS  PubMed  Google Scholar 

  106. Xu J, Jia L, Ma H, et al. Axl gene knockdown inhibits the metastasis properties of hepatocellular carcinoma via PI3K/Akt-PAK1 signal pathway. Tumor Biol. 2014;35:3809–17. doi:10.1007/s13277-013-1521-5.

    Article  CAS  Google Scholar 

  107. Elkabets M, Pazarentzos E, Juric D, et al. AXL mediates resistance to PI3Kα inhibition by activating the EGFR/PKC/mTOR axis in head and neck and esophageal squamous cell carcinomas. Cancer Cell. 2015;27:533–46. doi:10.1016/j.ccell.2015.03.010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Martinho O, Zucca LE, Reis RM. AXL as a modulator of sunitinib response in glioblastoma cell lines. Exp Cell Res. 2015;332:1–10. doi:10.1016/j.yexcr.2015.01.009.

    Article  CAS  PubMed  Google Scholar 

  109. Abu-Thuraia A, Gauthier R, Chidiac R, et al. Axl phosphorylates Elmo scaffold proteins to promote Rac activation and cell invasion. Mol Cell Biol. 2015;35:76–87. doi:10.1128/MCB.00764-14.

    Article  PubMed  CAS  Google Scholar 

  110. Seitz HM, Camenisch TD, Lemke G, et al. Macrophages and dendritic cells use different Axl/Mertk/Tyro3 receptors in clearance of apoptotic cells. J Immunol. 2007;178:5635–42.

    Article  CAS  PubMed  Google Scholar 

  111. Salian-Mehta S, Xu M, Wierman ME. AXL and MET crosstalk to promote gonadotropin releasing hormone (GnRH) neuronal cell migration and survival. Mol Cell Endocrinol. 2013;374:92–100. doi:10.1016/j.mce.2013.04.018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Paolino M, Choidas A, Wallner S, et al. The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells. Nature. 2014;507:508–12. doi:10.1038/nature12998.

    Article  CAS  PubMed  Google Scholar 

  113. 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 

  114. Georgescu MM, Kirsch KH, Shishido T, et al. Biological effects of c-Mer receptor tyrosine kinase in hematopoietic cells depend on the Grb2 binding site in the receptor and activation of NF-kappaB. Mol Cell Biol. 1999;19:1171–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Lee Y-J, Han J-Y, Byun J, et al. Inhibiting Mer receptor tyrosine kinase suppresses STAT1, SOCS1/3, and NF-kB activation and enhances inflammatory responses in lipopolysaccharide-induced acute lung injury. J Leukoc Biol. 2012;91:921–32. doi:10.1189/jlb.0611289.

    Article  CAS  PubMed  Google Scholar 

  116. Ye X, Li Y, Stawicki S, et al. An anti-Axl monoclonal antibody attenuates xenograft tumor growth and enhances the effect of multiple anticancer therapies. Oncogene. 2010;29:5254–64. doi:10.1038/onc.2010.268.

    Article  CAS  PubMed  Google Scholar 

  117. Krause S, Pfeiffer C, Strube S, et al. Mer tyrosine kinase promotes the survival of t(1;19)-positive acute lymphoblastic leukemia (ALL) in the central nervous system (CNS). Blood. 2015;125:820–30. doi:10.1182/blood-2014-06-583062.

    Article  CAS  PubMed  Google Scholar 

  118. Christoph S, Deryckere D, Schlegel J, et al. UNC569, a novel small-molecule mer inhibitor with efficacy against acute lymphoblastic leukemia in vitro and in vivo. Mol Cancer Ther. 2013;12:2367–77. doi:10.1158/1535-7163.MCT-13-0040.

    Article  CAS  PubMed  Google Scholar 

  119. Liu J, Zhang W, Stashko MA, et al. UNC1062, a new and potent Mer inhibitor. Eur J Med Chem. 2013;65:83–93. doi:10.1016/j.ejmech.2013.03.035.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Holland SJ, Pan A, Franci C, et al. R428, a selective small molecule inhibitor of Axl kinase, blocks tumor spread and prolongs survival in models of metastatic breast cancer. Cancer Res. 2010;70:1544–54. doi:10.1158/0008-5472.CAN-09-2997.

    Article  CAS  PubMed  Google Scholar 

  121. Pénzes K, Baumann C, Szabadkai I, et al. Combined inhibition of AXL, Lyn and p130Cas kinases block migration of triple negative breast cancer cells. Cancer Biol Ther. 2014;15:1571–82. doi:10.4161/15384047.2014.956634.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  122. Wilson C, Ye X, Pham T, et al. AXL inhibition sensitizes mesenchymal cancer cells to antimitotic drugs. Cancer Res. 2014;74:5878–90. doi:10.1158/0008-5472.CAN-14-1009.

    Article  CAS  PubMed  Google Scholar 

  123. Rankin EB, Fuh KC, Taylor TE, et al. AXL is an essential factor and therapeutic target for metastatic ovarian cancer. Cancer Res. 2010;70:7570–9. doi:10.1158/0008-5472.CAN-10-1267.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Kariolis MS, Miao YR, Jones DS, et al. An engineered Axl “decoy receptor” effectively silences the Gas6-Axl signaling axis. Nat Chem Biol. 2014;10:977–83. doi:10.1038/nchembio.1636.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Park I-K, 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 

  126. Rogers AEJ, Le JP, Sather S, et al. Mer receptor tyrosine kinase inhibition impedes glioblastoma multiforme migration and alters cellular morphology. Oncogene. 2012;31:4171–81. doi:10.1038/onc.2011.588.

    Article  CAS  PubMed  Google Scholar 

  127. Linger RMA, Lee-Sherick AB, DeRyckere D, et al. Mer receptor tyrosine kinase is a therapeutic target in pre-B-cell acute lymphoblastic leukemia. Blood. 2013;122:1599–609. doi:10.1182/blood-2013-01-478156.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Keating AK, Kim GK, Jones AE, et al. Inhibition of Mer and Axl receptor tyrosine kinases in astrocytoma cells leads to increased apoptosis and improved chemosensitivity. Mol Cancer Ther. 2010;9:1298–307. doi:10.1158/1535-7163.MCT-09-0707.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Linger RMA, Cohen RA, Cummings CT, et al. Mer or Axl receptor tyrosine kinase inhibition promotes apoptosis, blocks growth and enhances chemosensitivity of human non-small cell lung cancer. Oncogene. 2012. doi:10.1038/onc.2012.355.

    PubMed  PubMed Central  Google Scholar 

  130. Cummings CT, Linger RMA, Cohen RA, et al. Mer590, a novel monoclonal antibody targeting MER receptor tyrosine kinase, decreases colony formation and increases chemosensitivity in non-small cell lung cancer. Oncotarget. 2014;5:10434–45.

    Article  PubMed  PubMed Central  Google Scholar 

  131. Li Y, Ye X, Tan C, et al. Axl as a potential therapeutic target in cancer: role of Axl in tumor growth, metastasis and angiogenesis. Oncogene. 2009;28:3442–55. doi:10.1038/onc.2009.212.

    Article  CAS  PubMed  Google Scholar 

  132. Ruan G-X, Kazlauskas A. Axl is essential for VEGF-A-dependent activation of PI3K/Akt. EMBO J. 2012;31:1692–703. doi:10.1038/emboj.2012.21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Burstyn-Cohen T, Heeb MJ, Lemke G. Lack of protein S in mice causes embryonic lethal coagulopathy and vascular dysgenesis. J Clin Invest. 2009;119:2942–53. doi:10.1172/JCI39325.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Kasinski AL, Slack FJ. miRNA-34 prevents cancer initiation and progression in a therapeutically resistant K-ras and p53-induced mouse model of lung adenocarcinoma. Cancer Res. 2012;72:5576–87. doi:10.1158/0008-5472.CAN-12-2001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Mackiewicz M, Huppi K, Pitt JJ, et al. Identification of the receptor tyrosine kinase AXL in breast cancer as a target for the human miR-34a microRNA. Breast Cancer Res Treat. 2011;130:663–79. doi:10.1007/s10549-011-1690-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Mudduluru G, Ceppi P, Kumarswamy R, et al. 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 

  137. Li R, Shi X, Ling F, et al. MiR-34a suppresses ovarian cancer proliferation and motility by targeting AXL. Tumor Biol. 2015;36:7277–83. doi:10.1007/s13277-015-3445-8.

    Article  CAS  Google Scholar 

  138. Tian R, Xie X, Han J, et al. miR-199a-3p negatively regulates the progression of osteosarcoma through targeting AXL. Am J Cancer Res. 2014;4:738–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Png KJ, Halberg N, Yoshida M, Tavazoie SF. A microRNA regulon that mediates endothelial recruitment and metastasis by cancer cells. Nature. 2012;481:190–4. doi:10.1038/nature10661.

    Article  CAS  Google Scholar 

  140. Koorstra J-BM, Karikari CA, Feldmann G, et al. The Axl receptor tyrosine kinase confers an adverse prognostic influence in pancreatic cancer and represents a new therapeutic target. Cancer Biol Ther. 2009;8:618–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Gjerdrum C, Tiron C, Høiby T, et al. Axl is an essential epithelial-to-mesenchymal transition-induced regulator of breast cancer metastasis and patient survival. Proc Natl Acad Sci U S A. 2010;107:1124–9. doi:10.1073/pnas.0909333107.

    Article  CAS  PubMed  Google Scholar 

  142. Vuoriluoto K, Haugen H, Kiviluoto S, et al. Vimentin regulates EMT induction by Slug and oncogenic H-Ras and migration by governing Axl expression in breast cancer. Oncogene. 2011;30:1436–48. doi:10.1038/onc.2010.509.

    Article  CAS  PubMed  Google Scholar 

  143. Asiedu MK, Beauchamp-Perez FD, Ingle JN, et al. 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 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ian Dransfield .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Dransfield, I., Farnworth, S. (2016). Axl and Mer Receptor Tyrosine Kinases: Distinct and Nonoverlapping Roles in Inflammation and Cancer?. In: Gregory, C. (eds) Apoptosis in Cancer Pathogenesis and Anti-cancer Therapy. Advances in Experimental Medicine and Biology, vol 930. Springer, Cham. https://doi.org/10.1007/978-3-319-39406-0_5

Download citation

Publish with us

Policies and ethics