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Interactions of VEGF ligands and VEGF receptors

VEGF family of proteins
VEGF ligands, shown in purple boxes, bind to their associated receptors, leading to receptor dimerization and subsequent signal transduction. For example, 2 VEGFR-2 receptors with bound VEGF ligands would dimerize and be activated, causing phosphorylation of the receptor tyrosine kinase domains and a subsequent cellular signaling cascade that leads to angiogenesis. Of the primary receptors, VEGFR-2 is thought to mediate the majority of tumor angiogenic effects.1,2

Hicklin DJ, Ellis LM. J Clin Oncol. 2005;23:1011-1027. Reprinted with permission from the American Society of Clinical Oncology.

VEGF receptors

Vascular endothelial growth factor (VEGF) ligands mediate their angiogenic effects by binding to specific VEGF receptors, leading to receptor dimerization and subsequent signal transduction. VEGF ligands bind to 3 primary receptors and 2 co-receptors. Of the primary receptors, VEGFR-1 and VEGFR-2 are mainly associated with angiogenesis. The third primary receptor, VEGFR-3, is associated with lymphangiogenesis.1-3

Endothelial expression of VEGF receptors varies among the 3 primary receptors; VEGFR-2 is expressed on almost all endothelial cells, whereas VEGFR-1 and -3 are selectively expressed in distinct vascular beds.2 The neuropilin-1 (NP-1 or NRP-1) and NP-2 (or NRP-2) receptors are thought to increase the binding affinity of the various VEGF ligands to these primary receptors, although the specific roles of NP-1 and NP-2 in angiogenesis are not known.1-3

While VEGF receptors are well known to be present on the surface of endothelial cells, recent research suggests that they may also be expressed by tumor cells.2,4,5 The significance of this finding requires further investigation.

To learn more about each member of the VEGFR family of receptors, click on the links in the table below.

ReceptorActivityLigands
VEGFR-1Stimulates developmental (embryogenic) angiogenesisVEGF-A (VEGF)
VEGF-B
PlGF
VEGFR-2Mediates most downstream angiogenic effects of VEGFVEGF
VEGF-C
VEGF-D
VEGF-E
VEGFR-3Promotes lymphangiogenesisVEGF-C
VEGF-D

VEGFR-1

VEGFR-1 (Flt-1)

VEGF family of proteins
VEGFR-1, a key receptor during embryogenesis, does not appear to be critical to tumor angiogenesis.2

Hicklin DJ, Ellis LM. J Clin Oncol. 2005;23:1011-1027. Reprinted with permission from the American Society of Clinical Oncology.

Vascular endothelial growth factor (VEGF) receptor-1 (VEGFR-1) is a receptor for VEGF and can also bind VEGF-B and placental growth factor (PlGF). VEGFR-1 is a key receptor in developmental angiogenesis (ie, vessel formation during embryogenesis), but does not appear to be critical to pathogenic angiogenesis. Its role appears to vary with stages of development, physiologic and pathophysiologic conditions, and cell type.2,6

VEGFR-2

VEGFR-2 (Flk-1/KDR)

VEGFR-2 (Flk-1/KDR)
The majority of downstream angiogenic effects of VEGF, including endothelial cell proliferation, invasion, and migration, are mediated by VEGFR-2.2,7

Rini BI, Small EJ. J Clin Oncol. 2005;23:1028-1043. Reprinted with permission from the American Society of Clinical Oncology.

Vascular endothelial growth factor (VEGF) receptor-2 (VEGFR-2) mediates the majority of the downstream angiogenic effects of VEGF, including2:

  • Microvascular permeability
  • Endothelial cell proliferation
  • Invasion
  • Migration
  • Survival

Recent work suggests that VEGFR-2 can stimulate angiogenesis on its own. The activation and signaling of VEGFR-2 may be positively or negatively influenced by co-expression and activation of VEGFR-1.2,8

VEGFR-3

VEGFR-3 (Flt-4)

VEGF family of proteins
VEGFR-3 is found only in lymphatic endothelial cells in adults, and may be involved in the development of lymph node metastases.2,9-12

Hicklin DJ, Ellis LM. J Clin Oncol. 2005;23:1011-1027. Reprinted with permission from the American Society of Clinical Oncology.

Vascular endothelial growth factor (VEGF) receptor-3 (VEGFR-3) promotes lymphangiogenesis and is found only in lymphatic endothelial cells in adults. There is also evidence that VEGFR-3 plays a role in maintaining vascular integrity by modulating VEGFR-2 activity.2,9

VEGFR-3 activation has been observed in several solid tumor types, including melanoma and breast cancer. In these tumors, elevated levels of VEGFR-3 ligands VEGF-C and VEGF-D are associated with lymph node metastases.10-12

Next section

Postreceptor signaling

References:
1.

Ferrara N. Endocr Rev. 2004;25:581-611.

2.

Hicklin DJ, Ellis LM. J Clin Oncol. 2005;23:1011-1027.

3.

Kawasaki T, Kitsukawa T, Bekku Y, et al. Development. 1999;126:4895-4902.

4.

Ferrer FA, Miller LJ, Lindquist R, et al. Urology. 1999;54:567-572.

5.

Decaussin M, Sartelet H, Robert C, et al. J Pathol. 1999;188:369-377.

6.

Olofsson B, Korpelainen E, Pepper MS, et al. Proc Natl Acad Sci USA. 1998;95:11709-11714.

7.

Rini BI, Small EJ. J Clin Oncol. 2005;23:1028-1043.

8.

Ogawa S, Oku A, Sawano A, et al. J Biol Chem. 1998;273:31273-31282.

9.

Dumont DJ, Jussila L, Taipale J, et al. Science. 1998;282:946-949.

10.

Achen MG, Williams RA, Minekus MP, et al. J Pathol. 2001;193:147-154.

11.

Valtola R, Salven P, Heikkilä P, et al. Am J Pathol. 1999;154:1381-1390.

12.

Pepper MS, Tille JC, Nisato R, et al. Cell Tissue Res. 2003;314:167-177.