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VEGF(A protein that promotes angiogenesis and is known to be a prognostic factor in several types of tumour) receptors

Interactions of VEGF ligands and VEGFRs

VEGF ligands mediate their angiogenic effects by binding to specific VEGFRs, leading to receptor dimerisation(The coupling of two receptors, usually leading to activation and intracellular signalling) and subsequent signal transduction(The process by which an extracellular signaling molecule activates a membrane receptor that in turn alters intracellular molecules creating a response). VEGF ligands bind to three primary receptors and two co-receptors. Of the primary receptors, VEGFR-1 and VEGFR-2 are mainly associated with angiogenesis(The growth of new blood vessels from pre-existing vessels). The third primary receptor(Proteins located on the cell surface. When a specific molecule called a ligand binds to a receptor, signalling pathways are activated), VEGFR-3, is associated with lymphangiogenesis(The formation of lymphatic vessels from pre-existing lymphatic vessels, in a method believed to be similar to blood vessel development or angiogenesis).1,2

Endothelial expression of VEGFRs varies among the three 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(Cell surface glycoproteins that have been shown to serve as co-receptors for vascular endothelial growth factor (VEGF), suggesting a potential role in angiogenesis) (NP-1(Cell surface glycoproteins that have been shown to serve as co-receptors for vascular endothelial growth factor (VEGF), suggesting a potential role in angiogenesis) 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 VEGFRs are well known to be present on the surface of endothelial cells, recent research suggests that they may also be expressed by tumour(An abnormal growth of cells, forming a mass of tissue) cells.2,4,5 The significance of this finding requires further investigation.

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

VEGF family of receptors 

Receptor Activity Ligands
VEGFR-1 Stimulates developmental (embryogenic) angiogenesis VEGF-A (VEGF)
VEGFR-2 Mediates most downstream angiogenic effects of VEGF VEGF
VEGFR-3 Promotes lymphangiogenesis VEGF-C


VEGFR-1 can not only bind VEGF, but also VEGF-B and PlGF. VEGFR-1 is a key receptor in developmental angiogenesis (i.e. vessel formation during embryogenesis(The process by which the embryo is formed and develops, until it develops into a foetus)), but does not appear to be critical to pathogenic angiogenesis. Its role appears to vary with stages of development, physiological and pathophysiological conditions and cell type.2,6


VEGFR-2 mediates the majority of the downstream angiogenic effects of VEGF, including:2

  • Microvascular permeability
  • Endothelial cell proliferation(The reproduction of cells by multiplication of parts)
  • Invasion
  • Migration
  • Survival.

Recent work suggests that VEGFR-2 can be activated selectively by VEGF-E to stimulate angiogenesis on its own.8 The activation and signalling of VEGFR-2 may be positively or negatively influenced by co-expression and activation of VEGFR-1.2


VEGFR-3 promotes lymphangiogenesis and is found only in lymphatic endothelial cells in adults.2 There is also evidence that VEGFR-3 plays a role in maintaining vascular integrity by modulating VEGFR-2 activity.

VEGFR-3 activation has been observed in several solid tumour types, including melanoma and breast cancer. In these tumours, elevated levels of VEGFR-3 ligands VEGF-C and VEGF-D are associated with lymph node(Bodies of lymphoid tissue located along the course of lymphatic vessels; involved in the filtration of lymph) metastases.3–15

Post-receptor signalling in the VEGF pathway

Post-receptor signalling

Activation of VEGFRs can stimulate the expression of factors important for angiogenesis, including anti-apoptotic proteins, cell adhesion molecules, VEGFR-1, and MMPs. A large body of evidence suggests that VEGFR-2 is the most important of the VEGFRs with regard to angiogenesis, with post-receptor signalling pathways that promote endothelial cell division, permeability and survival. However, there seems to be a great deal of cross-talk in the signalling pathways – still only partially understood – that ultimately translates VEGFR binding into angiogenesis.1,16–19

"Extracellular signals modify intracellular processes through cognate receptors that elicit a cascade of events. However, a linear view of signal transduction falls short of describing all effects. Instead, branching, feedback, integration, and networking are characteristics of most if not all signal transduction pathways. Signalling cross-talk refers to a situation where one signal affects the output of another, seemingly distinct, signal transduction pathway."
Picard. Pure Appl Chem, 2003

To learn more about post-receptor signalling effects for each member of the VEGF family of receptors, click on the links below.

VEGF family of receptors 

Receptor Effects
VEGFR-1 Possible 'decoy receptor' effect
Induction of other factors
VEGFR-2 Proliferation
VEGFR-3 Effects mainly in lymphatic cells

Signalling through VEGFR-1

Though this was the first VEGFR to be identified, its function is still somewhat controversial.1,21

VEGFR-1 reveals a weak tyrosine autophosphorylation in response to VEGF. Some researchers have proposed that VEGFR-1 is a decoy receptor, and that it does not generally transmit mitogenic signals. Instead, these researchers propose that VEGFR-1 sequesters VEGF and prevents it from binding to VEGFR-2.1,16

Multiple findings also suggest that VEGFR-1 induces uPA, tPA, MMP9, and release of vascular bed-specific growth factors.1 Recent work by Lesslie and colleagues in CRC cell lines also suggests that VEGFR-1 promotes cancer cell migration through a pathway dependent on Src family kinases.22

Signalling through VEGFR-2

The mitogenic, angiogenic, and permeability-enhancing effects of VEGF are primarily mediated through VEGFR-2, which undergoes dimerisation and phosphorylation following ligand binding. This activity promotes the proliferation, migration and survival of endothelial cells.1

Specifically, the downstream signalling effects of VEGFR-2 binding include integrin activation via the PI3K/Akt pathway, as well as activation of the Raf/MEK/Erk pathway to induce endothelial cell growth.1

Signalling through VEGFR-3

VEGFR-3 is associated with lymphangiogenesis. When VEGF ligands bind with VEGFR-3, the complex triggers proliferation, migration, survival and lymphangiogenesis in lymphatic endothelial cells.1


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