Skip to main content
SpringerLink
Log in

The VEGF Receptor Family

  • Chapter
Receptor Tyrosine Kinases: Family and Subfamilies

  • 1762 Accesses

Abstract

The vascular endothelial growth factor (VEGF) family of ligands and receptors has been implicated in vascular development during embryogenesis. There is now a consensus that VEGF receptor signaling is also central to pathological angiogenesis associated with cancer, intraocular neovascular disorders, and other conditions. Advances in our understanding of the biology of VEGF pathway have led to the development and clinical applications of multiple VEGF-targeted therapies. A more comprehensive understanding of the VEGF ligands and receptors should shed further light on the molecular basis of vessel formation and improve outcomes of antiangiogenic therapies.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
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. Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1995;1(1):27–31.

    Article  CAS  PubMed  Google Scholar 

  2. Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature. 2000;407(6801):249–57.

    Article  CAS  PubMed  Google Scholar 

  3. Chung AS, Ferrara N. Developmental and pathological angiogenesis. Annu Rev Cell Dev Biol. 2011;27:563–84.

    Article  CAS  PubMed  Google Scholar 

  4. Chung AS, Lee J, Ferrara N. Targeting the tumour vasculature: insights from physiological angiogenesis. Nat Rev Cancer. 2010;10(7):505–14.

    Article  CAS  PubMed  Google Scholar 

  5. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9(6):669–76.

    Article  CAS  PubMed  Google Scholar 

  6. Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L. VEGF receptor signalling—in control of vascular function. Nat Rev Mol Cell biol. 2006;7(5):359–71.

    Article  CAS  PubMed  Google Scholar 

  7. Joukov V, Sorsa T, Kumar V, Jeltsch M, Claesson-Welsh L, Cao Y, et al. Proteolytic processing regulates receptor specificity and activity of VEGF-C. EMBO J. 1997;16(13):3898–911.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Lemmon MA, Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 2010;141(7):1117–34.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Matsumoto T, Claesson-Welsh L. VEGF receptor signal transduction. Science’s STKE. 2001;2001(112):21.

    Google Scholar 

  10. Carmeliet P. Angiogenesis in life, disease and medicine. Nature. 2005;438(7070):932–6.

    Article  CAS  PubMed  Google Scholar 

  11. Ferrara N, Hillan KJ, Gerber HP, Novotny W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov. 2004;3(5):391–400.

    Article  CAS  PubMed  Google Scholar 

  12. Ellis LM, Hicklin DJ. VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat Rev Cancer. 2008;8(8):579–91.

    Article  CAS  PubMed  Google Scholar 

  13. Ferrara N. Vascular endothelial growth factor and age-related macular degeneration: from basic science to therapy. Nat Med. 2010;16(10):1107–11.

    Article  CAS  PubMed  Google Scholar 

  14. Ferrara N, Carver-Moore K, Chen H, Dowd M, Lu L, O'Shea KS, et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature. 1996;380(6573):439–42.

    Article  CAS  PubMed  Google Scholar 

  15. Carmeliet P, Ferreira V, Breier G, Pollefeyt S, Kieckens L, Gertsenstein M, et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature. 1996;380(6573):435–9.

    Article  CAS  PubMed  Google Scholar 

  16. Gerber HP, Hillan KJ, Ryan AM, Kowalski J, Keller GA, Rangell L, et al. VEGF is required for growth and survival in neonatal mice. Development. 1999;126(6):1149–59.

    CAS  PubMed  Google Scholar 

  17. Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 1989;246(4935):1306–9.

    Article  CAS  PubMed  Google Scholar 

  18. Houck KA, Ferrara N, Winer J, Cachianes G, Li B, Leung DW. The vascular endothelial growth factor family: identification of a fourth molecular species and characterization of alternative splicing of RNA. Mol Endocrinol. 1991;5(12):1806–14.

    Article  CAS  PubMed  Google Scholar 

  19. Park JE, Keller GA, Ferrara N. The vascular endothelial growth factor (VEGF) isoforms: differential deposition into the subepithelial extracellular matrix and bioactivity of extracellular matrix-bound VEGF. Mol Biol Cell. 1993;4(12):1317–26.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Houck KA, Leung DW, Rowland AM, Winer J, Ferrara N. Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms. J Biol Chem. 1992;267(36):26031–7.

    CAS  PubMed  Google Scholar 

  21. Lee S, Jilani SM, Nikolova GV, Carpizo D, Iruela-Arispe ML. Processing of VEGF-A by matrix metalloproteinases regulates bioavailability and vascular patterning in tumors. J Cell Biol. 2005;169(4):681–91.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z. Vascular endothelial growth factor (VEGF) and its receptors. FASEB J. 1999;13(1):9–22.

    CAS  PubMed  Google Scholar 

  23. Carmeliet P, Ng YS, Nuyens D, Theilmeier G, Brusselmans K, Cornelissen I, et al. Impaired myocardial angiogenesis and ischemic cardiomyopathy in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188. Nat Med. 1999;5(5):495–502.

    Article  CAS  PubMed  Google Scholar 

  24. Ruhrberg C, Gerhardt H, Golding M, Watson R, Ioannidou S, Fujisawa H, et al. Spatially restricted patterning cues provided by heparin-binding VEGF-A control blood vessel branching morphogenesis. Genes Dev. 2002;16(20):2684–98.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Stalmans I, Ng YS, Rohan R, Fruttiger M, Bouche A, Yuce A, et al. Arteriolar and venular patterning in retinas of mice selectively expressing VEGF isoforms. J Clin Invest. 2002;109(3):327–36.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Maes C, Stockmans I, Moermans K, Van Looveren R, Smets N, Carmeliet P, et al. Soluble VEGF isoforms are essential for establishing epiphyseal vascularization and regulating chondrocyte development and survival. J Clin Invest. 2004;113(2):188–99.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Olofsson B, Pajusola K, von Euler G, Chilov D, Alitalo K, Eriksson U. Genomic organization of the mouse and human genes for vascular endothelial growth factor B (VEGF-B) and characterization of a second splice isoform. J Biol Chem. 1996;271(32):19310–7.

    Article  CAS  PubMed  Google Scholar 

  28. Persico MG, Vincenti V, DiPalma T. Structure, expression and receptor-binding properties of placenta growth factor (PlGF). Curr Top Microbiol Immunol. 1999;237:31–40.

    CAS  PubMed  Google Scholar 

  29. Dewerchin M, Carmeliet P. PlGF: a multitasking cytokine with disease-restricted activity. Cold Spring Harb Perspect Med. 2012;2(8).

    Google Scholar 

  30. Yang W, Ahn H, Hinrichs M, Torry RJ, Torry DS. Evidence of a novel isoform of placenta growth factor (PlGF-4) expressed in human trophoblast and endothelial cells. J Reprod Immunol. 2003;60(1):53–60.

    Article  CAS  PubMed  Google Scholar 

  31. Bellomo D, Headrick JP, Silins GU, Paterson CA, Thomas PS, Gartside M, et al. Mice lacking the vascular endothelial growth factor-B gene (Vegfb) have smaller hearts, dysfunctional coronary vasculature, and impaired recovery from cardiac ischemia. Circ Res. 2000;86(2):E29–35.

    Article  CAS  PubMed  Google Scholar 

  32. Hagberg CE, Falkevall A, Wang X, Larsson E, Huusko J, Nilsson I, et al. Vascular endothelial growth factor B controls endothelial fatty acid uptake. Nature. 2010;464(7290):917–21.

    Article  CAS  PubMed  Google Scholar 

  33. Hagberg CE, Mehlem A, Falkevall A, Muhl L, Fam BC, Ortsater H, et al. Targeting VEGF-B as a novel treatment for insulin resistance and type 2 diabetes. Nature. 2012;490(7420):426–30.

    Article  CAS  PubMed  Google Scholar 

  34. Carmeliet P, Moons L, Luttun A, Vincenti V, Compernolle V, De Mol M, et al. Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat Med. 2001;7(5):575–83.

    Article  CAS  PubMed  Google Scholar 

  35. Fischer C, Jonckx B, Mazzone M, Zacchigna S, Loges S, Pattarini L, et al. Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell. 2007;131(3):463–75.

    Article  CAS  PubMed  Google Scholar 

  36. Bais C, Wu X, Yao J, Yang S, Crawford Y, McCutcheon K, et al. PlGF blockade does not inhibit angiogenesis during primary tumor growth. Cell. 2010;141(1):166–77.

    Article  CAS  PubMed  Google Scholar 

  37. Ferrara N, Chen H, Davis-Smyth T, Gerber HP, Nguyen TN, Peers D, et al. Vascular endothelial growth factor is essential for corpus luteum angiogenesis. Nat Med. 1998;4(3):336–40.

    Article  CAS  PubMed  Google Scholar 

  38. Shojaei F, Wu X, Malik AK, Zhong C, Baldwin ME, Schanz S, et al. Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells. Nat Biotechnol. 2007;25(8):911–20.

    Article  CAS  PubMed  Google Scholar 

  39. Yao J, Wu X, Zhuang G, Kasman IM, Vogt T, Phan V, et al. Expression of a functional VEGFR-1 in tumor cells is a major determinant of anti-PlGF antibodies efficacy. Proc Natl Acad Sci USA. 2011;108(28):11590–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Karkkainen MJ, Haiko P, Sainio K, Partanen J, Taipale J, Petrova TV, et al. Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nat Immunol. 2004;5(1):74–80.

    Article  CAS  PubMed  Google Scholar 

  41. Baldwin ME, Halford MM, Roufail S, Williams RA, Hibbs ML, Grail D, et al. Vascular endothelial growth factor D is dispensable for development of the lymphatic system. Mol Cell Biol. 2005;25(6):2441–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Koch M, Dettori D, Van Nuffelen A, Souffreau J, Marconcini L, Wallays G, et al. VEGF-D deficiency in mice does not affect embryonic or postnatal lymphangiogenesis but reduces lymphatic metastasis. J Pathol. 2009;219(3):356–64.

    Article  CAS  PubMed  Google Scholar 

  43. Rissanen TT, Markkanen JE, Gruchala M, Heikura T, Puranen A, Kettunen MI, et al. VEGF-D is the strongest angiogenic and lymphangiogenic effector among VEGFs delivered into skeletal muscle via adenoviruses. Circ Res. 2003;92(10):1098–106.

    Article  CAS  PubMed  Google Scholar 

  44. Tammela T, Saaristo A, Holopainen T, Lyytikka J, Kotronen A, Pitkonen M, et al. Therapeutic differentiation and maturation of lymphatic vessels after lymph node dissection and transplantation. Nat Med. 2007;13(12):1458–66.

    Article  CAS  PubMed  Google Scholar 

  45. Jeltsch M, Kaipainen A, Joukov V, Meng X, Lakso M, Rauvala H, et al. Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science. 1997;276(5317):1423–5.

    Article  CAS  PubMed  Google Scholar 

  46. Veikkola T, Jussila L, Makinen T, Karpanen T, Jeltsch M, Petrova TV, et al. Signalling via vascular endothelial growth factor receptor-3 is sufficient for lymphangiogenesis in transgenic mice. EMBO J. 2001;20(6):1223–31.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Stacker SA, Caesar C, Baldwin ME, Thornton GE, Williams RA, Prevo R, et al. VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat Med. 2001;7(2):186–91.

    Article  CAS  PubMed  Google Scholar 

  48. Kopfstein L, Veikkola T, Djonov VG, Baeriswyl V, Schomber T, Strittmatter K, et al. Distinct roles of vascular endothelial growth factor-D in lymphangiogenesis and metastasis. Am J Pathol. 2007;170(4):1348–61.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Kurahara H, Takao S, Maemura K, Shinchi H, Natsugoe S, Aikou T. Impact of vascular endothelial growth factor-C and -D expression in human pancreatic cancer: its relationship to lymph node metastasis. Clin Cancer Res. 2004;10(24):8413–20.

    Article  CAS  PubMed  Google Scholar 

  50. Lohela M, Bry M, Tammela T, Alitalo K. VEGFs and receptors involved in angiogenesis versus lymphangiogenesis. Curr Opin Cell Biol. 2009;21(2):154–65.

    Article  CAS  PubMed  Google Scholar 

  51. Shibuya M, Claesson-Welsh L. Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis. Exp Cell Res. 2006;312(5):549–60.

    Article  CAS  PubMed  Google Scholar 

  52. Pajusola K, Aprelikova O, Pelicci G, Weich H, Claesson-Welsh L, Alitalo K. Signalling properties of FLT4, a proteolytically processed receptor tyrosine kinase related to two VEGF receptors. Oncogene. 1994;9(12):3545–55.

    CAS  PubMed  Google Scholar 

  53. Sawano A, Iwai S, Sakurai Y, Ito M, Shitara K, Nakahata T, et al. Flt-1, vascular endothelial growth factor receptor 1, is a novel cell surface marker for the lineage of monocyte-macrophages in humans. Blood. 2001;97(3):785–91.

    Article  CAS  PubMed  Google Scholar 

  54. Barleon B, Sozzani S, Zhou D, Weich HA, Mantovani A, Marme D. Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. Blood. 1996;87(8):3336–43.

    CAS  PubMed  Google Scholar 

  55. Dikov MM, Ohm JE, Ray N, Tchekneva EE, Burlison J, Moghanaki D, et al. Differential roles of vascular endothelial growth factor receptors 1 and 2 in dendritic cell differentiation. J Immunol. 2005;174(1):215–22.

    Article  CAS  PubMed  Google Scholar 

  56. Kaipainen A, Korhonen J, Pajusola K, Aprelikova O, Persico MG, Terman BI, et al. The related FLT4, FLT1, and KDR receptor tyrosine kinases show distinct expression patterns in human fetal endothelial cells. J Exp Med. 1993;178(6):2077–88.

    Article  CAS  PubMed  Google Scholar 

  57. Park JE, Chen HH, Winer J, Houck KA, Ferrara N. Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-1/KDR. J Biol Chem. 1994;269(41):25646–54.

    CAS  PubMed  Google Scholar 

  58. Waltenberger J, Claesson-Welsh L, Siegbahn A, Shibuya M, Heldin CH. Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor. J Biol Chem. 1994;269(43):26988–95.

    CAS  PubMed  Google Scholar 

  59. LeCouter J, Moritz DR, Li B, Phillips GL, Liang XH, Gerber HP, et al. Angiogenesis-independent endothelial protection of liver: role of VEGFR-1. Science. 2003;299(5608):890–3.

    Article  CAS  PubMed  Google Scholar 

  60. Fong GH, Rossant J, Gertsenstein M, Breitman ML. Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature. 1995;376(6535):66–70.

    Article  CAS  PubMed  Google Scholar 

  61. Fong GH, Zhang L, Bryce DM, Peng J. Increased hemangioblast commitment, not vascular disorganization, is the primary defect in flt-1 knock-out mice. Development. 1999;126(13):3015–25.

    CAS  PubMed  Google Scholar 

  62. Hiratsuka S, Minowa O, Kuno J, Noda T, Shibuya M. Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice. Proc Natl Acad Sci USA. 1998;95(16):9349–54.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  63. Clauss M, Weich H, Breier G, Knies U, Rockl W, Waltenberger J, et al. The vascular endothelial growth factor receptor Flt-1 mediates biological activities. Implications for a functional role of placenta growth factor in monocyte activation and chemotaxis. J Biol Chem. 1996;271(30):17629–34.

    Article  CAS  PubMed  Google Scholar 

  64. Jinnin M, Medici D, Park L, Limaye N, Liu Y, Boscolo E, et al. Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma. Nat Med. 2008;14(11):1236–46.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  65. Patten IS, Rana S, Shahul S, Rowe GC, Jang C, Liu L, et al. Cardiac angiogenic imbalance leads to peripartum cardiomyopathy. Nature. 2012;485(7398):333–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  66. Shalaby F, Rossant J, Yamaguchi TP, Gertsenstein M, Wu XF, Breitman ML, et al. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature. 1995;376(6535):62–6.

    Article  CAS  PubMed  Google Scholar 

  67. Shalaby F, Ho J, Stanford WL, Fischer KD, Schuh AC, Schwartz L, et al. A requirement for Flk1 in primitive and definitive hematopoiesis and vasculogenesis. Cell. 1997;89(6):981–90.

    Article  CAS  PubMed  Google Scholar 

  68. Phng LK, Gerhardt H. Angiogenesis: a team effort coordinated by notch. Dev Cell. 2009;16(2):196–208.

    Article  CAS  PubMed  Google Scholar 

  69. Gerhardt H, Golding M, Fruttiger M, Ruhrberg C, Lundkvist A, Abramsson A, et al. VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J Cell Biol. 2003;161(6):1163–77.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  70. Lobov IB, Renard RA, Papadopoulos N, Gale NW, Thurston G, Yancopoulos GD, et al. Delta-like ligand 4 (Dll4) is induced by VEGF as a negative regulator of angiogenic sprouting. Proc Natl Acad Sci USA. 2007;104(9):3219–24.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  71. Suchting S, Freitas C, le Noble F, Benedito R, Breant C, Duarte A, et al. The notch ligand delta-like 4 negatively regulates endothelial tip cell formation and vessel branching. Proc Natl Acad Sci USA. 2007;104(9):3225–30.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  72. Williams CK, Li JL, Murga M, Harris AL, Tosato G. Up-regulation of the notch ligand delta-like 4 inhibits VEGF-induced endothelial cell function. Blood. 2006;107(3):931–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  73. Kaipainen A, Korhonen J, Mustonen T, van Hinsbergh VW, Fang GH, Dumont D, et al. Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development. Proc Natl Acad Sci USA. 1995;92(8):3566–70.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  74. Kukk E, Lymboussaki A, Taira S, Kaipainen A, Jeltsch M, Joukov V, et al. VEGF-C receptor binding and pattern of expression with VEGFR-3 suggests a role in lymphatic vascular development. Development. 1996;122(12):3829–37.

    CAS  PubMed  Google Scholar 

  75. Karkkainen MJ, Ferrell RE, Lawrence EC, Kimak MA, Levinson KL, McTigue MA, et al. Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema. Nat Genet. 2000;25(2):153–9.

    Article  CAS  PubMed  Google Scholar 

  76. Irrthum A, Karkkainen MJ, Devriendt K, Alitalo K, Vikkula M. Congenital hereditary lymphedema caused by a mutation that inactivates VEGFR3 tyrosine kinase. Am J Hum Genet. 2000;67(2):295–301.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  77. Dumont DJ, Jussila L, Taipale J, Lymboussaki A, Mustonen T, Pajusola K, et al. Cardiovascular failure in mouse embryos deficient in VEGF receptor-3. Science. 1998;282(5390):946–9.

    Article  CAS  PubMed  Google Scholar 

  78. Haiko P, Makinen T, Keskitalo S, Taipale J, Karkkainen MJ, Baldwin ME, et al. Deletion of vascular endothelial growth factor C (VEGF-C) and VEGF-D is not equivalent to VEGF receptor 3 deletion in mouse embryos. Mol Cell Biol. 2008;28(15):4843–50.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  79. Tammela T, Zarkada G, Nurmi H, Jakobsson L, Heinolainen K, Tvorogov D, et al. VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling. Nat Cell Biol. 2011;13(10):1202–13.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  80. Galvagni F, Pennacchini S, Salameh A, Rocchigiani M, Neri F, Orlandini M, et al. Endothelial cell adhesion to the extracellular matrix induces c-Src-dependent VEGFR-3 phosphorylation without the activation of the receptor intrinsic kinase activity. Circ Res. 2010;106(12):1839–48.

    Article  CAS  PubMed  Google Scholar 

  81. Benedito R, Rocha SF, Woeste M, Zamykal M, Radtke F, Casanovas O, et al. Notch-dependent VEGFR3 upregulation allows angiogenesis without VEGF-VEGFR2 signalling. Nature. 2012;484(7392):110–4.

    Article  CAS  PubMed  Google Scholar 

  82. Zhang L, Zhou F, Han W, Shen B, Luo J, Shibuya M, et al. VEGFR-3 ligand-binding and kinase activity are required for lymphangiogenesis but not for angiogenesis. Cell Res. 2010;20(12):1319–31.

    Article  CAS  PubMed  Google Scholar 

  83. He Y, Kozaki K, Karpanen T, Koshikawa K, Yla-Herttuala S, Takahashi T, et al. Suppression of tumor lymphangiogenesis and lymph node metastasis by blocking vascular endothelial growth factor receptor 3 signaling. J Natl Cancer Inst. 2002;94(11):819–25.

    Article  CAS  PubMed  Google Scholar 

  84. Burton JB, Priceman SJ, Sung JL, Brakenhielm E, An DS, Pytowski B, et al. Suppression of prostate cancer nodal and systemic metastasis by blockade of the lymphangiogenic axis. Cancer Res. 2008;68(19):7828–37.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  85. Roberts N, Kloos B, Cassella M, Podgrabinska S, Persaud K, Wu Y, et al. Inhibition of VEGFR-3 activation with the antagonistic antibody more potently suppresses lymph node and distant metastases than inactivation of VEGFR-2. Cancer Res. 2006;66(5):2650–7.

    Article  CAS  PubMed  Google Scholar 

  86. Tammela T, Zarkada G, Wallgard E, Murtomaki A, Suchting S, Wirzenius M, et al. Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature. 2008;454(7204):656–60.

    Article  CAS  PubMed  Google Scholar 

  87. Padera TP, Kuo AH, Hoshida T, Liao S, Lobo J, Kozak KR, et al. Differential response of primary tumor versus lymphatic metastasis to VEGFR-2 and VEGFR-3 kinase inhibitors cediranib and vandetanib. Mol Cancer Ther. 2008;7(8):2272–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  88. Seetharam L, Gotoh N, Maru Y, Neufeld G, Yamaguchi S, Shibuya M. A unique signal transduction from FLT tyrosine kinase, a receptor for vascular endothelial growth factor VEGF. Oncogene. 1995;10(1):135–47.

    CAS  PubMed  Google Scholar 

  89. Gille H, Kowalski J, Yu L, Chen H, Pisabarro MT, Davis-Smyth T, et al. A repressor sequence in the juxtamembrane domain of Flt-1 (VEGFR-1) constitutively inhibits vascular endothelial growth factor-dependent phosphatidylinositol 3′-kinase activation and endothelial cell migration. EMBO J. 2000;19(15):4064–73.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  90. Selvaraj SK, Giri RK, Perelman N, Johnson C, Malik P, Kalra VK. Mechanism of monocyte activation and expression of proinflammatory cytochemokines by placenta growth factor. Blood. 2003;102(4):1515–24.

    Article  CAS  PubMed  Google Scholar 

  91. Ding Y, Huang Y, Song N, Gao X, Yuan S, Wang X, et al. NFAT1 mediates placental growth factor-induced myelomonocytic cell recruitment via the induction of TNF-alpha. J Immunol. 2010;184(5):2593–601.

    Article  CAS  PubMed  Google Scholar 

  92. Fan F, Wey JS, McCarty MF, Belcheva A, Liu W, Bauer TW, et al. Expression and function of vascular endothelial growth factor receptor-1 on human colorectal cancer cells. Oncogene. 2005;24(16):2647–53.

    Article  CAS  PubMed  Google Scholar 

  93. Taylor AP, Leon E, Goldenberg DM. Placental growth factor (PlGF) enhances breast cancer cell motility by mobilising ERK1/2 phosphorylation and cytoskeletal rearrangement. Br J Cancer. 2010;103(1):82–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  94. Koch S, Claesson-Welsh L. Signal transduction by vascular endothelial growth factor receptors. Cold Spring Harb Perspect Med. 2012;2(7):a006502.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  95. Solowiej J, Bergqvist S, McTigue MA, Marrone T, Quenzer T, Cobbs M, et al. Characterizing the effects of the juxtamembrane domain on vascular endothelial growth factor receptor-2 enzymatic activity, autophosphorylation, and inhibition by axitinib. Biochemistry. 2009;48(29):7019–31.

    Article  CAS  PubMed  Google Scholar 

  96. Kendall RL, Rutledge RZ, Mao X, Tebben AJ, Hungate RW, Thomas KA. Vascular endothelial growth factor receptor KDR tyrosine kinase activity is increased by autophosphorylation of two activation loop tyrosine residues. J Biol Chem. 1999;274(10):6453–60.

    Article  CAS  PubMed  Google Scholar 

  97. Matsumoto T, Bohman S, Dixelius J, Berge T, Dimberg A, Magnusson P, et al. VEGF receptor-2 Y951 signaling and a role for the adapter molecule TSAd in tumor angiogenesis. EMBO J. 2005;24(13):2342–53.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  98. Wu LW, Mayo LD, Dunbar JD, Kessler KM, Ozes ON, Warren RS, et al. VRAP is an adaptor protein that binds KDR, a receptor for vascular endothelial cell growth factor. J Biol Chem. 2000;275(9):6059–62.

    Article  CAS  PubMed  Google Scholar 

  99. Lamalice L, Houle F, Huot J. Phosphorylation of Tyr1214 within VEGFR-2 triggers the recruitment of Nck and activation of Fyn leading to SAPK2/p38 activation and endothelial cell migration in response to VEGF. J Biol Chem. 2006;281(45):34009–20.

    Article  CAS  PubMed  Google Scholar 

  100. Takahashi T, Yamaguchi S, Chida K, Shibuya M. A single autophosphorylation site on KDR/Flk-1 is essential for VEGF-A-dependent activation of PLC-gamma and DNA synthesis in vascular endothelial cells. EMBO J. 2001;20(11):2768–78.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  101. Cunningham SA, Arrate MP, Brock TA, Waxham MN. Interactions of FLT-1 and KDR with phospholipase C gamma: identification of the phosphotyrosine binding sites. Biochem Biophys Res Commun. 1997;240(3):635–9.

    Article  CAS  PubMed  Google Scholar 

  102. Holmqvist K, Cross MJ, Rolny C, Hagerkvist R, Rahimi N, Matsumoto T, et al. The adaptor protein shb binds to tyrosine 1175 in vascular endothelial growth factor (VEGF) receptor-2 and regulates VEGF-dependent cellular migration. J Biol Chem. 2004;279(21):22267–75.

    Article  CAS  PubMed  Google Scholar 

  103. Warner AJ, Lopez-Dee J, Knight EL, Feramisco JR, Prigent SA. The Shc-related adaptor protein, Sck, forms a complex with the vascular-endothelial-growth-factor receptor KDR in transfected cells. Biochem J. 2000;347(Pt 2):501–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  104. Sakurai Y, Ohgimoto K, Kataoka Y, Yoshida N, Shibuya M. Essential role of Flk-1 (VEGF receptor 2) tyrosine residue 1173 in vasculogenesis in mice. Proc Natl Acad Sci USA. 2005;102(4):1076–81.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  105. Cross MJ, Dixelius J, Matsumoto T, Claesson-Welsh L. VEGF-receptor signal transduction. Trends Biochem Sci. 2003;28(9):488–94.

    Article  CAS  PubMed  Google Scholar 

  106. Zhuang G, Yu K, Jiang Z, Chung A, Yao J, Ha C, et al. Phosphoproteomic analysis implicates the mTORC2-FoxO1 axis in VEGF signaling and feedback activation of receptor tyrosine kinases. Sci Signal. 2013;6(271):ra25.

    PubMed  Google Scholar 

  107. Dixelius J, Makinen T, Wirzenius M, Karkkainen MJ, Wernstedt C, Alitalo K, et al. Ligand-induced vascular endothelial growth factor receptor-3 (VEGFR-3) heterodimerization with VEGFR-2 in primary lymphatic endothelial cells regulates tyrosine phosphorylation sites. J Biol Chem. 2003;278(42):40973–9.

    Article  CAS  PubMed  Google Scholar 

  108. Salameh A, Galvagni F, Bardelli M, Bussolino F, Oliviero S. Direct recruitment of CRK and GRB2 to VEGFR-3 induces proliferation, migration, and survival of endothelial cells through the activation of ERK, AKT, and JNK pathways. Blood. 2005;106(10):3423–31.

    Article  CAS  PubMed  Google Scholar 

  109. Makinen T, Veikkola T, Mustjoki S, Karpanen T, Catimel B, Nice EC, et al. Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3. EMBO J. 2001;20(17):4762–73.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  110. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335–42.

    Article  CAS  PubMed  Google Scholar 

  111. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355(24):2542–50.

    Article  CAS  PubMed  Google Scholar 

  112. Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009;27(28):4733–40.

    Article  CAS  PubMed  Google Scholar 

  113. Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007;370(9605):2103–11.

    Article  PubMed  Google Scholar 

  114. Miles DW, Chan A, Dirix LY, Cortes J, Pivot X, Tomczak P, et al. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2010;28(20):3239–47.

    Article  CAS  PubMed  Google Scholar 

  115. Robert NJ, Dieras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, et al. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011;29(10):1252–60.

    Article  CAS  PubMed  Google Scholar 

  116. Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357(26):2666–76.

    Article  CAS  PubMed  Google Scholar 

  117. Kerbel R, Folkman J. Clinical translation of angiogenesis inhibitors. Nat Rev Cancer. 2002;2(10):727–39.

    Article  CAS  PubMed  Google Scholar 

  118. Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1419–31.

    Article  CAS  PubMed  Google Scholar 

  119. Brown DM, Kaiser PK, Michels M, Soubrane G, Heier JS, Kim RY, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1432–44.

    Article  CAS  PubMed  Google Scholar 

  120. Martin DF, Maguire MG, Fine SL, Ying GS, Jaffe GJ, Grunwald JE, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology. 2012;119(7):1388–98.

    Article  PubMed Central  PubMed  Google Scholar 

  121. Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, Jaffe GJ. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364(20):1897–908.

    Article  CAS  PubMed  Google Scholar 

  122. Ivy SP, Wick JY, Kaufman BM. An overview of small-molecule inhibitors of VEGFR signaling. Nat Rev Clin Oncol. 2009;6(10):569–79 [Review].

    Article  CAS  PubMed  Google Scholar 

  123. Zhang J, Yang PL, Gray NS. Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer. 2009;9(1):28–39.

    Article  PubMed  CAS  Google Scholar 

  124. Holash J, Davis S, Papadopoulos N, Croll SD, Ho L, Russell M, et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci USA. 2002;99(17):11393–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  125. Heier JS, Brown DM, Chong V, Korobelnik JF, Kaiser PK, Nguyen QD, et al. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology. 2012;119(12):2537–48.

    Article  PubMed  Google Scholar 

  126. Ohr M, Kaiser PK. Intravitreal aflibercept injection for neovascular (wet) age-related macular degeneration. Expert Opin Pharmacother. 2012;13(4):585–91.

    Article  CAS  PubMed  Google Scholar 

  127. Van Cutsem E, Tabernero J, Lakomy R, Prenen H, Prausova J, Macarulla T, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012;30(28):3499–506.

    Article  PubMed  CAS  Google Scholar 

  128. Ramlau R, Gorbunova V, Ciuleanu TE, Novello S, Ozguroglu M, Goksel T, et al. Aflibercept and Docetaxel versus Docetaxel alone after platinum failure in patients with advanced or metastatic non-small-cell lung cancer: a randomized, controlled phase III trial. J Clin Oncol. 2012;30(29):3640–7.

    Article  CAS  PubMed  Google Scholar 

  129. Campbell JP, Bressler SB, Bressler NM. Impact of availability of anti-vascular endothelial growth factor therapy on visual impairment and blindness due to neovascular age-related macular degeneration. Arch Ophthalmol. 2012;130(6):794–5.

    Article  PubMed  Google Scholar 

  130. Van Cutsem E, de Haas S, Kang YK, Ohtsu A, Tebbutt NC, Ming Xu J, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a biomarker evaluation from the AVAGAST randomized phase III trial. J Clin Oncol. 2012;30(17):2119–27.

    Article  PubMed  CAS  Google Scholar 

  131. Brauer MJ, Zhuang G, Schmidt M, Yao J, Wu X, Kaminker JS, et al. Identification and analysis of in vivo VEGF downstream markers link VEGF pathway activity with efficacy of anti-VEGF therapies. Clin Cancer Res. 2013;19(13):3681–92.

    Article  CAS  PubMed  Google Scholar 

  132. Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer. 2008;8(8):592–603.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  133. Jain RK, Duda DG, Willett CG, Sahani DV, Zhu AX, Loeffler JS, et al. Biomarkers of response and resistance to antiangiogenic therapy. Nat Rev Clin Oncol. 2009;6(6):327–38.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  134. Tol J, Koopman M, Cats A, Rodenburg CJ, Creemers GJ, Schrama JG, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med. 2009;360(6):563–72.

    Article  CAS  PubMed  Google Scholar 

  135. Hecht JR, Mitchell E, Chidiac T, Scroggin C, Hagenstad C, Spigel D, et al. A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol. 2009;27(5):672–80.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Genentech Inc, 1 DNA Way, South San Francisco, CA, 94080, USA

    Guanglei Zhuang

  2. Department of Pathology, Moores Cancer Center, University of California San Diego, La Jolla, CA, 92093, USA

    Napoleone Ferrara

Authors
  1. Guanglei Zhuang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Napoleone Ferrara
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Napoleone Ferrara .

Editor information

Editors and Affiliations

  1. School of Medicine and Public Health Department of Human Oncology, University of Wisconsin, Madison, Wisconsin, USA

    Deric L. Wheeler

  2. Department of Biological Regulation, Rehovot, Israel

    Yosef Yarden

Receptor at a glance: VEGFR1

Receptor at a glance: VEGFR1

Chromosome location

13q12

Gene size (bp)

194,744

Intron/exon numbers

29/30

mRNA size (5′, ORF, 3′)

285, 4017, 2821

Amino acid number

1,338

kDa

151

Posttranslational modifications

Y794, Y1048, Y1053, Y1169, Y1213,

Y1242, Y1327, Y1333 phosphorylation

Domains

7 immunoglobulin (Ig)-like domains

1 transmembrane domain

1 kinase domain

Ligands

VEGFA, VEGFB, PlGF

Known dimerization partners

VEGFR1, VEGFR2,

neuropilin-1, neuropilin-2

Pathways activated

PI3K, MAPK, NFAT

Tissues expressed

Vascular endothelial cells

Placental trophoblast cells

Peripheral blood monocytes

Human diseases

Peripartum cardiomyopathy

Cancer

Knockout mouse phenotype

Die in utero at mid-somite stages due to abnormal vascular channels

Receptor at a glance: VEGFR2

Chromosome location

4q11–q12

Gene size (bp)

47,113

Intron/exon numbers

29/30

mRNA size (5′, ORF, 3′)

302, 4071, 1982

Amino acid number

1,356

kDa

152

Posttranslational modifications

Y951, Y996, Y1054, Y1059, Y1175,

Y1214, Y1238 phosphorylation

Domains

7 immunoglobulin (Ig)-like domains

1 transmembrane domain

1 kinase domain

Ligands

VEGFA, VEGFC, VEGFD

Known dimerization partners

VEGFR1, VEGFR2, VEGFR3,

Neuropilin-1, neuropilin-2

Pathways activated

PI3K, MAPK, PLCG1, NOS3, SRC

Tissues expressed

Vascular endothelial cells

Hematopoietic stem cells

Endocardial cells

Human diseases

Hemangioma capillary infantile

Cancer

Vascular diseases

Knockout mouse phenotype

Die in utero due to early defects in the development of hematopoietic and endothelial cells

Receptor at a glance: VEGFR3

Chromosome location

5q35.3

Gene size (bp)

48,119

Intron/exon numbers

29/30

mRNA size (5′, ORF, 3′)

79, 4092, 1686

Amino acid number

1,363

kDa

153

Posttranslational modifications

Y517, T532, Y1230, Y1231, Y1265,

Y1333, Y1337, Y1363 phosphorylation

Domains

7 immunoglobulin (Ig)-like domains

1 transmembrane domain

1 kinase domain

Ligands

VEGFC, VEGFD

Known dimerization partners

VEGFR2, VEGFR3, neuropilin-2

Pathways activated

PI3K, MAPK, JUN

Tissues expressed

Vascular endothelial cells

Lymphatic endothelial cells

Human diseases

Lymphedema hereditary type 1A

Hemangioma capillary infantile

Cancer

Knockout mouse phenotype

Die in utero due to defective blood vessel development and cardiovascular failure

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Zhuang, G., Ferrara, N. (2015). The VEGF Receptor Family. In: Wheeler, D., Yarden, Y. (eds) Receptor Tyrosine Kinases: Family and Subfamilies. Springer, Cham. https://doi.org/10.1007/978-3-319-11888-8_18

Download citation

Publish with us

Policies and ethics

Search

Navigation