Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Tie receptors: new modulators of angiogenic and lymphangiogenic responses

Nature Reviews Molecular Cell Biology volume 2, pages 257–267 (2001)Cite this article

Abstract

Angiogenesis is required for normal embryonic vascular development and aberrant angiogenesis contributes to several diseases, including cancer, diabetes and tissue ischaemia. What are the molecular mechanisms that regulate this important process? The Tie family of receptors and their ligands, the angiopoietins, are beginning to provide insight into how vessels make decisions such as whether to grow or regress — processes that are important not only during development but throughout an organism's life.

Key Points

  • Endothelial-cell-specific receptor tyrosine kinases can be subgrouped into the Tie and vascular endothelial growth factor (VEGF) receptor families. The Tie receptor family has two members, Tie1 and Tie2.

  • Tie receptors are required for the angiogenic remodelling of vessels during embryonic development and for vessel stabilization in quiescent adult vasculature.

  • Tie receptors also contribute to the abnormal vascular growth that is associated with many pathological conditions such as venous malformations, tumour growth and rheumatoid arthritis.

  • Signal-transduction pathways controlled by the Tie receptors are overlapping but independent as Tie1 and Tie2 do not seem to functionally compensate for one another.

  • Angiopoietins, the ligands for the Tie2 receptor, might have either agonistic (Ang1 and Ang4) or antagonistic (Ang3) actions regulating vascular expansion and survival. Ang2 can stimulate or inhibit angiogenesis in different contexts. In addition, it seems to be important for the development of lymphatic vessels.

  • Ang1 facilitates phosphatidylinositol-3-OH kinase (PI(3)K)-dependent endothelial cell survival through stimulation of the serine–threonine kinase Akt, leading to protection from apoptosis.

  • Ang1 also stimulates endothelial cell migration, sprouting and tubule formation. Endothelial cell motility induced by Tie2 activation seems to be regulated through activation of the PI(3)K, the adaptor protein Nck and focal adhesion kinase.

  • Three tyrosine phosphatases participating in the regulation of Tie2 receptor signalling have been characterized.

  • Tie1 signal transduction has been difficult to study as no ligand for this receptor has been identified. However, recent studies indicate that Tie1 participates in ligand-independent signalling. Tie1 might also form heterodimers with Tie2 and therefore modulate Tie2 signalling.

  • Increasing our knowledge of Tie receptor signalling pathways might lead to the development of more effective and refined targets for angiogenic therapies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Blood and lymph vascular systems.
Figure 2: Structure of endothelial-cell receptor tyrosine kinases and growth factors involved in vasculogenesis, angiogenesis and lymphangiogenesis.
Figure 3: The angiopoietins.
Figure 4: Venous malformation associated with a TIE2 mutation.
Figure 5: Regulatory elements of Tie1 and Tie2 genes.
Figure 6: Tie2 signal transduction, showing the known binding partners for Tie2.

Similar content being viewed by others

References

  1. Witte, M. H., Way, D. L., Witte, C. L. & Bernas, M. Lymphangiogenesis: mechanisms, significance and clinical implications. EXS 79, 65–112 (1997).

    CAS  PubMed  Google Scholar 

  2. Soker, S., Takashima, S., Miao, H. Q., Neufeld, G. & Klagsbrun, M. Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 92, 735–745 (1998).

    CAS  PubMed  Google Scholar 

  3. Jeltsch, M. et al. Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science 276, 1423–1425 (1997).

    CAS  PubMed  Google Scholar 

  4. Karkkainen, M. J., Jussila, L., Ferrell, R. E., Finegold, D. N. & Alitalo, K. Molecular regulation of lymphangiogenesis and targets for tissue oedema. Trends Mol. Med. 7, 18–22 (2001).

    CAS  PubMed  Google Scholar 

  5. Mandriota, S. J. et al. Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis. EMBO J. 20, 672–682 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Stacker, S. A. et al. Vascular endothelial growth factor-D promotes the metastatic spread of cancer via the lymphatics. Nature Med. 7, 136–191 (2001).

    Google Scholar 

  7. Skobe, M. et al. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nature Med. 7, 192–198 (2001)

    CAS  PubMed  Google Scholar 

  8. Karkkainen, M. J. et al. Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema. Nature Genet. 25, 153–159 (2000).

    CAS  PubMed  Google Scholar 

  9. Makinen, T. et al. Inhibition of lymphangiogenesis with resulting lymphoedema in transgenic mice expressing soluble VEGF receptor-3. Nature Med. 7, 199–205 (2001)

    CAS  PubMed  Google Scholar 

  10. Davis, S. et al. Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell 87, 1161–1169 (1996).Description of the isolation of the first ligand for the Tie2 receptor using a new expression cloning technique.

    CAS  PubMed  Google Scholar 

  11. Maisonpierre, P. C. et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277, 55–60 (1997).Shows that Ang2 is an antagonist of Tie2, providing the first evidence that related growth factors might have opposing actions towards receptor tyrosine kinases in vertebrates.

    CAS  PubMed  Google Scholar 

  12. Valenzuela, D. M. et al. Angiopoietins 3 and 4: diverging gene counterparts in mice and humans. Proc. Natl Acad. Sci. USA 96, 1904–1909 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Shalaby, F. et al. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 376, 62–66 (1995).

    CAS  PubMed  Google Scholar 

  14. Fong, G. H., Rossant, J., Gertsenstein, M. & Breitman, M. L. Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 376, 66–70 (1995).

    CAS  PubMed  Google Scholar 

  15. Dumont, D. J. et al. Dominant-negative and targeted null mutations in the endothelial receptor tyrosine kinase, tek, reveal a critical role in vasculogenesis of the embryo. Genes Dev. 8, 1897–1909 (1994).Description of the importance of Tie2 in regulating the survival and integrity of the endothelium during development.

    CAS  PubMed  Google Scholar 

  16. Sato, T. N. et al. Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation. Nature 376, 70–74 (1995).Describes the importance of Tie1 and Tie2 in vascular integrity and remodelling during embryogenesis, respectively.

    CAS  PubMed  Google Scholar 

  17. Suri, C. et al. Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell 87, 1171–1180 (1996).Shows that Ang1-deficient mice have a similar phenotype to Tie2-deficient mice and implies that Ang1 is required for endothelial–periendothelial paracrine communication during vascular development.

    CAS  PubMed  Google Scholar 

  18. Patan, S. TIE1 and TIE2 receptor tyrosine kinases inversely regulate embryonic angiogenesis by the mechanism of intussusceptive microvascular growth. Microvasc. Res. 56, 1–21 (1998).

    CAS  PubMed  Google Scholar 

  19. Puri, M., Rossant, J., Alitalo, K., Bernstein, A. & Partanen, J. The receptor tyrosine kinase TIE is required for integrity and survival of vascular endothelial cells. EMBO J. 14, 5884–5891 (1995).Describes the essential role of Tie1 in controlling the integrity of the embryonic microvascular endothelium.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Puri, M. C., Partanen, J., Rossant, J. & Bernstein, A. Interaction of the TEK and TIE receptor tyrosine kinases during cardiovascular development. Development 126, 4569–4580 (1999).Shows that the functions mediated by the Tie1 and Tie2 receptors are not redundant through analysis of chimeric embryos. An interesting endocardial developmental phenotype is also revealed.

    CAS  PubMed  Google Scholar 

  21. Partanen, J. et al. Cell autonomous functions of the receptor tyrosine kinase TIE in a late phase of angiogenic capillary growth and endothelial cell survival during murine development. Development 122, 3013–3021 (1996).

    CAS  PubMed  Google Scholar 

  22. Suri, C. et al. Increased vascularization in mice overexpressing angiopoietin-1. Science 282, 468–471 (1998).

    CAS  PubMed  Google Scholar 

  23. Thurston, G. et al. Leakage-resistant blood vessels in mice transgenically overexpressing angiopoietin-1. Science 286, 2511–2514 (1999).Shows that Ang1 can block vascular permeability induced by VEGF.

    CAS  PubMed  Google Scholar 

  24. Jones, N. et al. Rescue of the early vascular defects in Tek/Tie2 null mice reveals an essential survival function. EMBO Rep. (in the press).

  25. Wong, A. L. et al. Tie2 expression and phosphorylation in angiogenic and quiescent adult tissues. Circ. Res. 81, 567–574 (1997).

    CAS  PubMed  Google Scholar 

  26. Alon, T. et al. Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity. Nature Med. 1, 1024–1028 (1995).

    CAS  PubMed  Google Scholar 

  27. Benjamin, L. E., Hemo, I. & Keshet, E. A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF. Development 125, 1591–1598 (1998).

    CAS  PubMed  Google Scholar 

  28. Holash, J. et al. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 284, 1994–1998 (1999).Shows that Ang2 is associated with tumour angiogenesis in a model where the tumour co-opts existing host vessels.

    CAS  PubMed  Google Scholar 

  29. Stratmann, A., Risau, W. & Plate, K. H. Cell type-specific expression of angiopoietin-1 and angiopoietin-2 suggests a role in glioblastoma angiogenesis. Am. J. Pathol. 153, 1459–1466 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Zagzag, D. et al. In situ expression of angiopoietins in astrocytomas identifies angiopoietin-2 as an early marker of tumor angiogenesis. Exp. Neurol. 159, 391–400 (1999).

    CAS  PubMed  Google Scholar 

  31. Brown, L. F., Dezube, B. J., Tognazzi, K., Dvorak, H. F. & Yancopoulos, G. D. Expression of Tie1, Tie2, and angiopoietins 1, 2, and 4 in Kaposi's sarcoma and cutaneous angiosarcoma. Am. J. Pathol. 156, 2179–2183 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Asahara, T. et al. Tie2 receptor ligands, angiopoietin-1 and angiopoietin-2, modulate VEGF-induced postnatal neovascularization. Circ. Res. 83, 233–240 (1998).

    CAS  PubMed  Google Scholar 

  33. Teichert-Kuliszewska, K. et al. Biological actions of angiopoietin-1 and–2 in a fibrin matrix model of angiogenesis. Cardiovasc. Res. 49, 659–670 (2001).

    CAS  PubMed  Google Scholar 

  34. Kim, I. et al. Angiopoietin-2 at high concentration can enhance endothelial cell survival through the phosphatidylinositol 3′-kinase/Akt signal transduction pathway. Oncogene 19, 4549–4552 (2000).

    CAS  PubMed  Google Scholar 

  35. Vikkula, M. et al. Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2. Cell 87, 1181–1190 (1996).Finds an activating mutation in the Tie2 kinase domain associated with venous malformations in two unrelated families.

    CAS  PubMed  Google Scholar 

  36. Calvert, J. T. et al. Allelic and locus heterogeneity in inherited venous malformations. Hum. Mol. Genet. 8, 1279–1289 (1999).

    CAS  PubMed  Google Scholar 

  37. Korpelainen, E. I., Karkkainen, M., Gunji, Y., Vikkula, M. & Alitalo, K. Endothelial receptor tyrosine kinases activate the STAT signaling pathway: mutant Tie-2 causing venous malformations signals a distinct STAT activation response. Oncogene 18, 1–8 (1999).

    CAS  PubMed  Google Scholar 

  38. Kaipainen, A. et al. Enhanced expression of the tie receptor tyrosine kinase messenger RNA in the vascular endothelium of metastatic melanomas. Cancer Res. 54, 6571–6577 (1994).

    CAS  PubMed  Google Scholar 

  39. Hatva, E. et al. Expression of endothelial cell-specific receptor tyrosine kinases and growth factors in human brain tumors. Am. J. Pathol. 146, 368–378 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Salven, P. et al. Endothelial Tie growth factor receptor provides antigenic marker for assessment of breast cancer angiogenesis. Br. J. Cancer 74, 69–72 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Peters, K. G. et al. Expression of Tie2/Tek in breast tumour vasculature provides a new marker for evaluation of tumour angiogenesis. Br. J. Cancer 77, 51–56 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Korhonen, J. et al. Enhanced expression of the tie receptor tyrosine kinase in endothelial cells during neovascularization. Blood 80, 2548–2555 (1992).

    CAS  PubMed  Google Scholar 

  43. Kukk, E. et al. Analysis of Tie receptor tyrosine kinase in haemopoietic progenitor and leukaemia cells. Br. J. Haematol. 98, 195–203 (1997).

    CAS  PubMed  Google Scholar 

  44. Oh, H. et al. Hypoxia and vascular endothelial growth factor selectively up-regulate angiopoietin-2 in bovine microvascular endothelial cells. J. Biol. Chem. 274, 15732–15739 (1999).

    CAS  PubMed  Google Scholar 

  45. Mandriota, S. J. & Pepper, M. S. Regulation of angiopoietin-2 mRNA levels in bovine microvascular endothelial cells by cytokines and hypoxia. Circ. Res. 83, 852–859 (1998).

    CAS  PubMed  Google Scholar 

  46. McCarthy, M. J., Crowther, M., Bell, P. R. & Brindle, N. P. The endothelial receptor tyrosine kinase tie-1 is upregulated by hypoxia and vascular endothelial growth factor. FEBS Lett. 423, 334–338 (1998).

    CAS  PubMed  Google Scholar 

  47. Tian, H., McKnight, S. L. & Russell, D. W. Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes Dev. 11, 72–82 (1997).

    CAS  PubMed  Google Scholar 

  48. Willam, C. et al. Tie2 receptor expression is stimulated by hypoxia and proinflammatory cytokines in human endothelial cells. Circ. Res. 87, 370–377 (2000).

    CAS  PubMed  Google Scholar 

  49. Schlaeger, T. M. et al. Uniform vascular-endothelial-cell-specific gene expression in both embryonic and adult transgenic mice. Proc. Natl Acad. Sci. USA 94, 3058–3063 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Iljin, K. et al. Role of ets factors in the activity and endothelial cell specificity of the mouse Tie gene promoter. FASEB J. 13, 377–386 (1999).

    CAS  PubMed  Google Scholar 

  51. Lin, P. et al. Antiangiogenic gene therapy targeting the endothelium-specific receptor tyrosine kinase Tie2. Proc. Natl Acad. Sci. USA 95, 8829–8834 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Lin, P. et al. Inhibition of tumor angiogenesis using a soluble receptor establishes a role for Tie2 in pathologic vascular growth. J. Clin. Invest. 100, 2072–2078 (1997).References 51 and 52 indicate that Tie2 might be useful in tumour therapy.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Siemeister, G. et al. Two independent mechanisms essential for tumor angiogenesis: inhibition of human melanoma xenograft growth by interfering with either the vascular endothelial growth factor receptor pathway or the Tie-2 pathway. Cancer Res. 59, 3185–3191 (1999).

    CAS  PubMed  Google Scholar 

  54. Millauer, B., Shawver, L. K., Plate, K. H., Risau, W. & Ullrich, A. Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant. Nature 367, 576–579 (1994).

    CAS  PubMed  Google Scholar 

  55. Huang, L., Turck, C. W., Rao, P. & Peters, K. G. GRB2 and SH-PTP2: potentially important endothelial signaling molecules downstream of the TEK/TIE2 receptor tyrosine kinase. Oncogene 11, 2097–2103 (1995).

    CAS  PubMed  Google Scholar 

  56. Jones, N. et al. Identification of Tek/Tie2 binding partners. Binding to a multifunctional docking site mediates cell survival and migration. J. Biol. Chem. 274, 30896–30905 (1999).

    CAS  PubMed  Google Scholar 

  57. Koblizek, T. I., Weiss, C., Yancopoulos, G. D., Deutsch, U. & Risau, W. Angiopoietin-1 induces sprouting angiogenesis in vitro. Curr. Biol. 8, 529–532 (1998).

    CAS  PubMed  Google Scholar 

  58. Witzenbichler, B., Maisonpierre, P. C., Jones, P., Yancopoulos, G. D. & Isner, J. M. Chemotactic properties of angiopoietin-1 and -2, ligands for the endothelial-specific receptor tyrosine kinase Tie2. J. Biol. Chem. 273, 18514–18521 (1998).

    CAS  PubMed  Google Scholar 

  59. Kwak, H. J., So, J. N., Lee, S. J., Kim, I. & Koh, G. Y. Angiopoietin-1 is an apoptosis survival factor for endothelial cells. FEBS Lett. 448, 249–253 (1999).

    CAS  PubMed  Google Scholar 

  60. Kontos, C. D. et al. Tyrosine 1101 of Tie2 is the major site of association of p85 and is required for activation of phosphatidylinositol 3-kinase and Akt. Mol. Cell Biol. 18, 4131–4140 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Fujikawa, K., de Aos Scherpenseel, I., Jain, S. K., Presman, E. & Varticovski, L. Role of PI 3-kinase in angiopoietin-1-mediated migration and attachment-dependent survival of endothelial cells. Exp. Cell Res. 253, 663–672 (1999).

    CAS  PubMed  Google Scholar 

  62. Kim, I. et al. Angiopoietin-1 regulates endothelial cell survival through the phosphatidylinositol 3′-kinase/Akt signal transduction pathway. Circ. Res. 86, 24–29 (2000).

    CAS  PubMed  Google Scholar 

  63. Hayes, A. J. et al. Angiopoietin-1 and its receptor tie-2 participate in the regulation of capillary-like tubule formation and survival of endothelial cells. Microvasc. Res. 58, 224–237 (1999).

    CAS  PubMed  Google Scholar 

  64. Papapetropoulos, A. et al. Direct actions of angiopoietin-1 on human endothelium: evidence for network stabilization, cell survival, and interaction with other angiogenic growth factors. Lab. Invest. 79, 213–223 (1999).

    CAS  PubMed  Google Scholar 

  65. Jiang, B. H., Zheng, J. Z., Aoki, M. & Vogt, P. K. Phosphatidylinositol 3-kinase signaling mediates angiogenesis and expression of vascular endothelial growth factor in endothelial cells. Proc. Natl Acad. Sci. USA 97, 1749–1753 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Papapetropoulos, A. et al. Angiopoietin-1 inhibits endothelial cell apoptosis via the Akt/survivin pathway. J. Biol. Chem. 275, 9102–9105 (2000).

    CAS  PubMed  Google Scholar 

  67. Speliotes, E. K., Uren, A., Vaux, D. & Horvitz, H. R. The survivin-like C. elegans BIR-1 protein acts with the Aurora-like kinase AIR-2 to affect chromosomes and the spindle midzone. Mol. Cell 6, 211–223 (2000).

    CAS  PubMed  Google Scholar 

  68. Gerber, H. P. et al. Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3′-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation. J. Biol. Chem. 273, 30336–30343 (1998).

    CAS  PubMed  Google Scholar 

  69. Kim, I. et al. Angiopoietin-1 induces endothelial cell sprouting through the activation of focal adhesion kinase and plasmin secretion. Circ. Res. 86, 952–959 (2000).

    CAS  PubMed  Google Scholar 

  70. Jones, N. & Dumont, D. J. The Tek/Tie2 receptor signals through a novel Dok-related docking protein, Dok-R. Oncogene 17, 1097–1108 (1998).

    CAS  PubMed  Google Scholar 

  71. Huang, L. et al. HCPTPA, a protein tyrosine phosphatase that regulates vascular endothelial growth factor receptor-mediated signal transduction and biological activity. J. Biol. Chem. 274, 38183–38188 (1999).

    CAS  PubMed  Google Scholar 

  72. Fachinger, G., Deutsch, U. & Risau, W. Functional interaction of vascular endothelial-protein-tyrosine phosphatase with the angiopoietin receptor tie-2. Oncogene 18, 5948–5953 (1999).

    CAS  PubMed  Google Scholar 

  73. Shewchuk, L. M. et al. Structure of the Tie2 RTK domain. Self-inhibition by the nucleotide binding loop, activation loop, and C-terminal tail. Struct. Fold Des. 8, 1105–1113 (2001).

    Google Scholar 

  74. Yabkowitz, R. et al. Regulation of tie receptor expression on human endothelial cells by protein kinase C-mediated release of soluble tie. Blood 90, 706–715 (1997).

    CAS  PubMed  Google Scholar 

  75. McCarthy, M. J. et al. Potential roles of metalloprotease mediated ectodomain cleavage in signaling by the endothelial receptor tyrosine kinase Tie-1. Lab. Invest. 79, 889–895 (1999).

    CAS  PubMed  Google Scholar 

  76. Yabkowitz, R. et al. Inflammatory cytokines and vascular endothelial growth factor stimulate the release of soluble tie receptor from human endothelial cells via metalloprotease activation. Blood 93, 1969–1979 (1999).

    CAS  PubMed  Google Scholar 

  77. Marron, M. B., Hughes, D. P., McCarthy, M. J., Beaumont, E. R. & Brindle, N. P. Tie-1 receptor tyrosine kinase endodomain interaction with SHP2: potential signalling mechanisms and roles in angiogenesis. Adv. Exp. Med. Biol. 476, 35–46 (2000).

    CAS  PubMed  Google Scholar 

  78. Marron, M. B., Hughes, D. P., Edge, M. D., Forder, C. L. & Brindle, N. P. Evidence for heterotypic interaction between the receptor tyrosine kinases tie-1 and tie–2. J. Biol. Chem. 275, 39741–39746 (2000).

    CAS  PubMed  Google Scholar 

  79. Thurston, G. et al. Angiopoietin-1 protects the adult vasculature against plasma leakage. Nature Med. 6, 460–463 (2000).

    CAS  PubMed  Google Scholar 

  80. Partanen, J. et al. A novel endothelial cell surface receptor tyrosine kinase with extracellular epidermal growth factor homology domains. Mol. Cell. Biol. 12, 1698–1707 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Dumont, D. J., Gradwohl, G. J., Fong, G. H., Auerbach, R. & Breitman, M. L. The endothelial-specific receptor tyrosine kinase, tek, is a member of a new subfamily of receptors. Oncogene 8, 1293–1301 (1993).

    CAS  PubMed  Google Scholar 

  82. Gerber, H. P. et al. VEGF is required for growth and survival in neonatal mice. Development 126, 1149–1159 (1999).

    CAS  PubMed  Google Scholar 

  83. Gerber, H. P. et al. VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Nature Med. 5, 623–628 (1999).

    CAS  PubMed  Google Scholar 

  84. Ferrara, N. et al. Vascular endothelial growth factor is essential for corpus luteum angiogenesis. Nature Med. 4, 336–340 (1998).

    CAS  PubMed  Google Scholar 

  85. Pe'er, J. et al. Upregulated expression of vascular endothelial growth factor in proliferative diabetic retinopathy. Br. J. Ophthalmol. 80, 241–245 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Iwama, A. et al. Molecular cloning and characterization of mouse TIE and TEK receptor tyrosine kinase genes and their expression in hematopoietic stem cells. Biochem. Biophys. Res. Commun. 195, 301–309 (1993).

    CAS  PubMed  Google Scholar 

  87. Rodewald, H. R. & Sato, T. N. Tie1, a receptor tyrosine kinase essential for vascular endothelial cell integrity, is not critical for the development of hematopoietic cells. Oncogene 12, 397–404 (1996).

    CAS  PubMed  Google Scholar 

  88. Takakura, N. et al. Critical role of the TIE2 endothelial cell receptor in the development of definitive hematopoiesis. Immunity 9, 677–686 (1998).Associates Tie2 with the regulation of haematopoiesis.

    CAS  PubMed  Google Scholar 

  89. Takakura, N. et al. A role for hematopoietic stem cells in promoting angiogenesis. Cell 102, 199–209 (2001).

    Google Scholar 

  90. Carmeliet, P. et al. Targeted deficiency or cytosolic truncation of the VE-cadherin gene in mice impairs VEGF-mediated endothelial survival and angiogenesis. Cell 98, 147–157 (1999).

    CAS  PubMed  Google Scholar 

  91. Wiesener, M. S. et al. Induction of endothelial PAS domain protein-1 by hypoxia: characterization and comparison with hypoxia-inducible factor-1α. Blood 92, 2260–2268 (1998).

    CAS  PubMed  Google Scholar 

  92. Claffey, K. P. et al. Identification of a human VPF/VEGF 3′ untranslated region mediating hypoxia-induced mRNA stability. Mol. Biol. Cell 9, 469–481 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Maltepe, E., Schmidt, J. V., Baunoch, D., Bradfield, C. A. & Simon, M. C. Abnormal angiogenesis and responses to glucose and oxygen deprivation in mice lacking the protein ARNT. Nature 386, 403–407 (1997).

    CAS  PubMed  Google Scholar 

  94. Ryan, H. E., Lo, J. & Johnson, R. S. HIF-1α is required for solid tumor formation and embryonic vascularization. EMBO J. 17, 3005–3015 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Peng, J., Zhang, L., Drysdale, L. & Fong, G. H. The transcription factor EPAS-1/hypoxia-inducible factor 2α plays an important role in vascular remodeling. Proc. Natl Acad. Sci. USA 97, 8386–8391 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Ravi, R. et al. Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1α. Genes Dev. 14, 34–44 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Carmeliet, P. et al. Role of HIF-1α in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 394, 485–490 (1998).

    CAS  PubMed  Google Scholar 

  98. Maxwell, P. H. et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399, 271–275 (1999).

    CAS  PubMed  Google Scholar 

  99. Lisztwan, J., Imbert, G., Wirbelauer, C., Gstaiger, M. & Krek, W. The von Hippel-Lindau tumor suppressor protein is a component of an E3 ubiquitin-protein ligase activity. Genes Dev. 13, 1822–1833 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Graeber, T. G. et al. Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature 379, 88–91 (1996).

    CAS  PubMed  Google Scholar 

  101. Procopio, W. N., Pelavin, P. I., Lee, W. M. & Yeilding, N. M. Angiopoietin-1 and-2 coiled coil domains mediate distinct homo-oligomerization patterns, but fibrinogen-like domains mediate ligand activity. J. Biol. Chem. 274, 30196–30201 (1999).

    CAS  PubMed  Google Scholar 

  102. Huang, Y. Q., Li, J. J. & Karpatkin, S. Identification of a family of alternatively spliced mRNA species of angiopoietin-1. Blood 95, 1993–1999 (2000).

    CAS  PubMed  Google Scholar 

  103. Kim, I. et al. Characterization and expression of a novel alternatively spliced human angiopoietin-2. J. Biol. Chem. 275, 18550–18556 (2000).

    CAS  PubMed  Google Scholar 

  104. Mezquita, J., Mezquita, B., Pau, M. & Mezquita, C. Characterization of a novel form of angiopoietin-2 (Ang-2B) and expression of VEGF and angiopoietin-2 during chicken testicular development and regression. Biochem. Biophys. Res. Commun. 260, 492–498 (1999).

    CAS  PubMed  Google Scholar 

  105. Korhonen, J. et al. Endothelial-specific gene expression directed by the tie gene promoter in vivo. Blood 86, 1828–1835 (1995).

    CAS  PubMed  Google Scholar 

  106. Schlaeger, T. M., Qin, Y., Fujiwara, Y., Magram, J. & Sato, T. N. Vascular endothelial cell lineage-specific promoter in transgenic mice. Development 121, 1089–1098 (1995).

    CAS  PubMed  Google Scholar 

  107. Jones, N. & Dumont, D. J. Recruitment of Dok-R to the EGF receptor through its PTB domain is required for attenuation of Erk MAP kinase activation. Curr. Biol. 9, 1057–1060 (1999).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank G. Yancopoulos, C. Kontos, M. Detmar and Z. Master for discussions of unpublished data. The authors also acknowledge the support of the Canadian Institutes of Health Research (the former Medical Research Council (MRC) of Canada), the National Cancer Institute of Canada, the Juvenile Diabetes Foundation International and Cancer Care Ontario to D.J.D. D.J.D. is a scientist of the MRC of Canada. N.J. was supported by an MRC studentship award. K.I. and K.A. are supported by the Finnish Academy, the Sigrid Juselieus Foundation, the University of Helsinki Hospital, the State Technology Development Center as well as by EU Biomed programme. We apologize for the failure to cite many important contributions to this field owing to space limitations.

Author information

Authors and Affiliations

  1. Department of Medical Biophysics, University of Toronto, Sunnybrook and Women's College Health Sciences Centre, 2075 Bayview Avenue, S-227, Toronto, M4N 3M5, Ontario, Canada

    Nina Jones & Daniel J. Dumont

  2. Molecular/Cancer Biology Laboratory, Ludwig Institute for Cancer Research, Biomedicum Institute, University of Helsinki, P.O. Box 21 (Haartmaninkatu 3), Helsinki, SF-00014, Finland

    Kristiina Iljin & Kari Alitalo

Authors
  1. Nina Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kristiina Iljin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Daniel J. Dumont
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kari Alitalo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kari Alitalo.

Related links

Related links

DATABASE LINKS

VEGF

VEGFR-1

VEGFR-2

VEGFR-3

neuropilin-1

VEGF-C

VEGF-D

angiopoietins

Tie2

Tie1

Ang1

Ang4

Ang2

Ang3

HIF-2

Grb2

MAPK

Akt

Bad

caspase-9

nitric oxide synthase

survivin

BIR-1

FAK

MMP-2

Dok-R

Pak

Grb7

Shp2

protein kinase C

ANG2443

aANG2B

mAng3

cadherins

selectins

integrins

VE-cadherin

α-catenin

β-catenin

γ-catenin

vinculin

α-actinin

Sos

CAS

paxillin

HIF-1α

HIF-1β

HIF-2α

p53

Mdm2

Glossary

MESODERM

Third germ layer in the embryo, formed during the process of gastrulation.

PRIMARY CAPILLARY PLEXUS

Simplified, honeycomb-like network of rudimentary blood vessels that is especially evident in the yolk sac vasculature.

PERIENDOTHELIAL SUPPORT CELLS

Mesenchymal cells that surround the endothelial component of mature blood vessels. They include pericytes and vascular smooth muscle cells.

PERICYTES

Support cells of capillaries (referred to as smooth muscle cells in larger vessels).

LYMPHANGIOGENESIS

Development and growth of lymphatic vessels.

STROMA

Connective tissue made up of cells, such as fibroblasts, and matrix, such as collagen.

LYMPHOEDEMA

Disease caused by obstruction or defects of the lymphatic vessels, resulting in accumulation of interstitial tissue fluid.

ENDOCARDIUM

Endothelial lining of the cardiac lumen.

SRC

Cytoplasmic tyrosine kinase first identified as a transforming oncogene in an avian retrovirus. This kinase is the prototypic kinase from which src-homology regions were first described.

ANOIKIS

Induction of programmed cell death by detachment of cells from the extracellular matrix.

FIBRIN MATRICES

Cell-culture substratum used in in vitro assays of angiogenesis to examine endothelial cell differentiation. Based on the premise that endothelial cells invade blood clots during wound repair and that fibrin is the major component of a blood clot.

OEDEMA

Accumulation of tissue fluid leading to swelling.

STATS

Family of cytoplasmic transcription factors (signal transducers and activators of transcription) that dimerize upon phosphorylation and translocate to the nucleus to activate transcription of target genes.

GLIOBLASTOMA

Malignant brain tumour, predominantly located in the cerebral hemispheres.

KAPOSI'S SARCOMA

Angiogenic tumour composed of endothelial and spindle cells (elongated fibroblast-like shaped cells that usually express endothelial markers).

ETS

Group of winged helix–loop–helix transcription factors that contain an ETS DNA-binding domain.

CHORIOALLANTOIC MEMBRANE

An extremely vascular envelope created by fusion of the allantoic membrane with the chorion. Functions in the exchange of wastes and metabolites in the embryo.

NCK

SH2/SH3-domain-containing adaptor molecule that has been implicated in cell migration through transduction of signals to the actin cytoskeleton.

SHP2

SH2-domain-containing cytoplasmic tyrosine phosphatase.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jones, N., Iljin, K., Dumont, D. et al. Tie receptors: new modulators of angiogenic and lymphangiogenic responses. Nat Rev Mol Cell Biol 2, 257–267 (2001). https://doi.org/10.1038/35067005

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/35067005

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing