VEGFR

The vascular endothelial growth factor receptor (VEGFR) family comprises in humans three endothelial cell (EC) specific tyrosine kinase receptors (VEGFR-1, VEGFR-2 and VEGFR-3). VEGFRs are the major direct mediators of proliferation of blood vascular endothelial cells (BECs) and lymphatic endothelial cells (LECs). Individual VEGFRs become activated by different subsets of the vascular endothelial growth factor (VEGF) family.

VEGFR-2 is the central mediator of the formation (vasculogenesis), growth (angiogenesis) and maintenance of blood vessels. It is also a marker for the common precursors of blood and endothelial cells (hemangioblasts). VEGFR-2 continues to be expressed in the differentiated endothelial lineage, but is downregulated by hematopoietic cells. The importance of VEGFR-2 for vasculogenesis and hematopoiesis is seen in knock-out mice that fail to develop both blood islands and blood vessels.

In contrast to VEGFR-2, VEGFR-1 has a more limited scope of action. In fact, it was thought that all functions of VEGF except for its chemoattractive role for monocytes were mediated exclusively by VEGFR-2. VEGFR-2 selective VEGF mutants or viral homologues are fully active EC mitogens, whereas VEGF family members or mutants which bind only to VEGFR-1 largely lack the ability to promote EC growth. Mice lacking the tyrosine kinase domain of VEGFR-1 are normal; only the VEGF-induced migration of their macrophages is reduced in vitro. However, complete ablation of VEGFR-1 results in embryonic lethality because increased endothelial precursor proliferation leads to a disorganized vasculature. Based on these results, VEGFR-1 was previously regarded as a decoy receptor with negligible signaling properties. However, later reports indicated that there was a more complex interplay between VEGFR-1 and VEGFR-2 including heterodimerization in pathological angiogenesis.

In early embryogenesis all three VEGFRs are expressed in endothelial cells. Concomitantly with the development of the lymphatic vessels VEGFR-3 becomes restricted to the lymphatic endothelium. While the ligand binding characteristics of VEGFR-1 and VEGFR-2 are conserved between humans and mice, VEGFR-3 shows more interspecies variability: in humans both VEGFR-3 ligands (VEGF-C and VEGF-D) are also capable of activating VEGFR-2 and are therefore potentially angiogenic, whereas mouse VEGF-D can only activate VEGFR-3. Moreover, in higher primates a retroviral insertion into the VEGFR-3 gene has led to the emergence of two splice isoforms, which differ in their signaling properties.

Of the seven extracellular Ig-like domains of VEGFRs, the three N-terminal ones are responsible for ligand binding; further deletion of at least one domain is tolerated without significant loss of affinity. The functions of the remaining extracellular domains are less well defined; however a duplication event within these domains marks the evolutionary segregation between the VEGF and the PDGF/CSF-1/SCF receptor families.

Due to the central role of endothelial cells in both cardiovascular and neoplastic disease, VEGFRs have been used as targets for both pro- and antiangiogenic therapy. Proangiogenic therapy has mostly employed various VEGFs or modified versions thereof to stimulate VEGFR signaling. Antiangiogenic therapy can target VEGFRs at three different levels: (i) soluble forms of the receptor ("ligand traps") can sequester receptor agonists (a method that nature itself uses to downregulate VEGF signaling), (ii) molecules (antibodies, aptamers, small peptides, dominant negative receptors, synthetic compounds) can block agonist binding or receptor dimerization and (iii) specific inhibitors can block the tyrosine kinase activity (ATP analogs) or critical transphosphorylation sites (small peptides, nonphosphorylatable peptide analogs).

 

The Table below contains accepted modulators and additional information. For a list of additional products, see the "Similar Products" section below.

 

Family Members VEGFR-1 VEGFR-2 VEGFR-3
Other Names Flt-1
Fms-like tyrosine Kinase 1
KDR
Flk-1
Kinase insert domain containing receptor
Fetal liver kinase 1
Flt-4
Fms-like tyrosine kinase 4
Molecular Weight
(kDa)
~180 kDa
200-230 kDa
~195 kDa (120+75a; VEGFR-3s)
Structural Data 1312 aa (VEGFR-1); 661 aa (sVEGFR-1) 1337 aa 1340 aa (VEGFR-3l); 1275 aa (VEGFR-3s)
Isoforms VEGFR-1
sVEGFR-1 (soluble form)
Not Known VEGFR-3l
VEGFR-3s
Species Presumed ubiquitous in vertebrates
Invertebrate homologs exist
Presumed ubiquitous in vertebrates
Invertebrate homologs exist
Presumed ubiquitous in vertebrates
Invertebrate homologs exist
Domain
Organization
7 extracellular IgSF domains
Single transmembrane domain
Split intracellular tyrosine kinase domain
7 extracellular IgSF domains
Single transmembrane domain
Split intracellular tyrosine kinase domain
7 extracellular IgSF domains
Single transmembrane domain
Split intracellular tyrosine kinase domain
Phosphorylation
Sites
Tyr794
Tyr1169
Tyr1213
Tyr1242
Tyr1327
Tyr1333
Tyr951
Tyr1059
Tyr1054
Tyr1175
Tyr1214
Tyr1305 (minor)
Tyr1309 (minor)
Tyr1319 (minor)
Tyr1063
Tyr1068
Tyr1230
Tyr1231
Tyr1265
Tyr1337
Tyr1363
Tissue
Distribution
BECs
Hematopoietic stem cells
Monocytes/macrophages
Osteoclasts
Spermatogenic and Leydig cells
BECs
LECs
Hematopoietic stem cells
Megakaryocytes
LECs
Fenestrated BECs
HEVs
Tumor endothelium
Subcellular
Localization
Plasma membrane Plasma membrane Plasma membrane
Binding Partners/
Associated Proteins
NRP-1
NRP-2
VEGFR-2
NRP-1
NRP-2
αvβ3 integrin
VE-cadherin
VEGFR-1
VEGFR-3
VRAP
Sck
PLCγ
Shc
Sos
SHP-2
p85
PLCγ
VEGFR-2
Grb2
Upstream
Activators
VEGFbg
PlGF
VEGF-Bb,c
VEGF
VEGF-Cd,e
VEGF-Df,g
VEGF-E
svVEGF
VEGF-Ce
VEGF-Df
Downstream
Activation
NO release
STATs
Erk
Akt/PKB
MAPK
Src
FAK
STATs
NO
Erk
Akt/PKB
MAPK
Activators Not Known Not Known Not Known
Inhibitorsh SU5416 (Semaxinib) (S8442)
SU6668
SU11657
SU11248
ZD6474
PTK787 (ZK222584;Vatalanib)
AAL993 (ZK260255)
SU10944
CP-547,632
SU5416 (Semaxinib) (S8442)
SU6668
SU11657
SU11248
ZD6474
PTK787 (ZK222584;Vatalanib)
AAL993 (ZK260255)
SU10944
CP-547,632
SU5416 (Semaxinib) (S8442)
SU6668
SU11657
SU11248
ZD6474
PTK787 (ZK222584;Vatalanib)
AAL993 (ZK260255)
MAZ51i
Selective
Inhibitors
Bevacizumab (VEGF monoclonal antibody, Avastin)
VEGF-TRAP (soluble chimeric VEGFR)
VGA1102 (ligand binding inhibitor)
Bevacizumab (VEGF monoclonal antibody, Avastin)
VEGF-TRAP (soluble chimeric VEGFR)
VGA1102 (ligand binding inhibitor)
Not Known
Selective
Activators
Not Known Not Known Not Known
Physiological
Function
Vascular development
Vascular permeability
Receptor for VEGF, PlGF and VEGF-B
Vascular development
Vascular permeability
Receptor for VEGF, VEGF-C, VEGF-D, VEGF-E and svVEGF
Critical role in tumor-associated angiogenesis
Receptor for VEGF-C and VEGF-D
Lymphangiogenesis
Embryonic angiogenesis/vasculogenesis
Disease
Relevance
Not Known Angiogenesis (or lack thereof) in diabetic retinopathy
Psoriasis
Rheumatoid arthritis
Tumor growth
Cardiovascular disease
Tumor metastasis
Germ line mutations in some families of type I hereditary
Lymphedema

 

Footnotes

a) The extracellular domain is cleaved into two polypeptides but remains connected via a disulfide bridge.

b) Splice isoforms differ in their ability to bind heparan sulfate proteoglycans, distribution and biological function.

c) Also called VRF.

d) High affinity binding requires proteolytic processing.

e) Also called VRP or VEGF-2.

f) Also called FIGF.

g) Also called VEGF-A or VPF.

h) Due to the large number of different tyrosine kinases, the specificity of tyrosine kinase inhibitors cannot be tested exhaustively; tyrosine kinases known to be affected are given in brackets; for several inhibitors, differences between assays have been reported (isolated kinase assays vesus cell-based assays versus in-vivo assays).

i) Inhibits also other not yet identified kinase(s).

j) Also called VEGF-A or VPF.

 

Abbreviations

BEC: Blood vascular endothelial cell
CSF-1: Colony-stimulating factor-1
FIGF: c-fos induced growth factor
HEV: High endothelial venules
LEC: Lymphatic endothelial cell
NRP: Neuropilin
PDGF: Platelet-derived growth factor
PlGF: Placenta growth factor
SCF: Scatter factor
svVEGF: Snake venom VEGF
VEGF: Vascular endothelial growth factor
VEGFR: VEGF receptor
VPF: Vascular permeability factor (VEGF)
VRF: VEGF-Related factor (VEGF-B)
VRP: VEGF-Related protein (VEGF-C)

 

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References