Signaling by VEGF (Homo sapiens)

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3, 7, 20, 222, 12, 13, 15, 21...17, 2012, 9, 12, 16, 214-6, 11, 15...8, 10, 14, 18, 19PGF dimer VEGFC dimer VEGF-A,C,D dimers VEGFC,VEGFD dimers NRP2VEGFR1 dimer VEGFC dimer VEGFD dimer VEGFC dimer PGF dimer VEGFB dimer VEGF VEGFA dimer VEGFD dimer VEGFA dimer VEGFC,VEGFD dimers VEGFR1 dimer VEGFD dimer VEGFR3 dimer VEGFA dimer VEGFR3 dimerVEGFC, VEGFD dimers VEGFR1 dimer VEGFA, VEGFB, PGF dimers VEGFB dimer VEGFC dimer VEGFR2VEGFA,C,D VEGFR1 dimerVEGFA, VEGFB, PGF dimers VEGFA dimer VEGFR2 dimer VEGFA, VEGFB, PGF dimers VEGFD dimer cytosolVEGF-A,C,D dimers VEGFR2 dimer VEGF dimer NRP1VEGFR2 dimer FIGF VEGFA VEGFR2VEGFA,C,DVEGFR1 dimerVEGFA, VEGFB, PGF dimersFLT1KDR VEGFB VEGF dimerVEGFC FLT1 FIGF FLT1 KDRNRP2 PGF FIGF VEGFA VEGFC VEGF-A,C,D dimersNRP2VEGFR1 dimerVEGFA NRP1VEGFR2 dimerPGF FIGF VEGFB NRP1VEGFB VEGFC,VEGFD dimersNRP1 VEGFA KDR PGF VEGFVEGFA, VEGFB, PGF dimersVEGFC NRP2VEGFA FLT4 FLT4VEGFC VEGFR3 dimerVEGFC, VEGFD dimersVEGFC FIGF


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In normal development vascular endothelial growth factors (VEGFs) are crucial regulators of vascular development during embryogenesis (vasculogenesis) and blood-vessel formation in the adult (angiogenesis). In tumor progression, activation of VEGF pathways promotes tumor vascularization, facilitating tumor growth and metastasis. Abnormal VEGF function is also associated with inflammatory diseases including atherosclerosis, and hyperthyroidism. The members of the VEGF and VEGF-receptor protein families have distinct but overlapping ligand-receptor specificities, cell-type expression, and function. VEGF-receptor activation in turn regulates a network of signaling processes in the body that promote endothelial cell growth, migration and survival (Hicklin and Ellis, 2005; Shibuya and Claesson-Welsh, 2006).
Molecular features of the VGF signaling cascades are outlined in the figure below (from Olsson et al. 2006; Nature Publishing Group). Tyrosine residues in the intracellular domains of VEGF receptors 1, 2,and 3 are indicated by dark blue boxes; residues susceptible to phosphorylation are numbered. A circled R indicates that phosphorylation is regulated by cell state (VEGFR2), by ligand binding (VEGFR1), or by heterodimerization (VEGFR3). Specific phosphorylation sites (boxed numbers) bind signaling molecules (dark blue ovals), whose interaction with other cytosolic signaling molecules (light blue ovals) leads to specific cellular (pale blue boxes) and tissue-level (pink boxes) responses in vivo. Signaling cascades whose molecular details are unclear are indicated by dashed arrows. DAG, diacylglycerol; EC, endothelial cell; eNOS, endothelial nitric oxide synthase; FAK, focal adhesion kinase; HPC, hematopoietic progenitor cell; HSP27, heat-shock protein-27; MAPK, mitogen-activated protein kinase; MEK, MAPK and ERK kinase; PI3K, phosphatidylinositol 3' kinase; PKC, protein kinase C; PLCgamma, phospholipase C-gamma; Shb, SH2 and beta-cells; TSAd, T-cell-specific adaptor.
In the current release, the first events in these cascades - the interactions between VEGF proteins and their receptors - are annotated. Details of signaling events and their biological outcome, concisely illustrated in the image below, will be available in future versions of this pathway.

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  120. Andjelković M, Alessi DR, Meier R, Fernandez A, Lamb NJ, Frech M, Cron P, Cohen P, Lucocq JM, Hemmings BA.; ''Role of translocation in the activation and function of protein kinase B.''; PubMed Europe PMC Scholia
  121. Holmqvist K, Cross M, Riley D, Welsh M.; ''The Shb adaptor protein causes Src-dependent cell spreading and activation of focal adhesion kinase in murine brain endothelial cells.''; PubMed Europe PMC Scholia
  122. Tang PA, Moore MJ.; ''Aflibercept in the treatment of patients with metastatic colorectal cancer: latest findings and interpretations.''; PubMed Europe PMC Scholia
  123. Tuteja N, Chandra M, Tuteja R, Misra MK.; ''Nitric Oxide as a Unique Bioactive Signaling Messenger in Physiology and Pathophysiology.''; PubMed Europe PMC Scholia
  124. Ferrara N, Damico L, Shams N, Lowman H, Kim R.; ''Development of ranibizumab, an anti-vascular endothelial growth factor antigen binding fragment, as therapy for neovascular age-related macular degeneration.''; PubMed Europe PMC Scholia
  125. Abu-Ghazaleh R, Kabir J, Jia H, Lobo M, Zachary I.; ''Src mediates stimulation by vascular endothelial growth factor of the phosphorylation of focal adhesion kinase at tyrosine 861, and migration and anti-apoptosis in endothelial cells.''; PubMed Europe PMC Scholia
  126. Gratton JP, Fontana J, O'Connor DS, Garcia-Cardena G, McCabe TJ, Sessa WC.; ''Reconstitution of an endothelial nitric-oxide synthase (eNOS), hsp90, and caveolin-1 complex in vitro. Evidence that hsp90 facilitates calmodulin stimulated displacement of eNOS from caveolin-1.''; PubMed Europe PMC Scholia
  127. Aghazadeh B, Lowry WE, Huang XY, Rosen MK.; ''Structural basis for relief of autoinhibition of the Dbl homology domain of proto-oncogene Vav by tyrosine phosphorylation.''; PubMed Europe PMC Scholia
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  129. Nava VE, Lacana E, Poulton S, Liu H, Sugiura M, Kono K, Milstien S, Kohama T, Spiegel S.; ''Functional characterization of human sphingosine kinase-1.''; PubMed Europe PMC Scholia
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History

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CompareRevisionActionTimeUserComment
114739view16:22, 25 January 2021ReactomeTeamReactome version 75
113183view11:25, 2 November 2020ReactomeTeamReactome version 74
112411view15:35, 9 October 2020ReactomeTeamReactome version 73
101315view11:20, 1 November 2018ReactomeTeamreactome version 66
100852view20:52, 31 October 2018ReactomeTeamreactome version 65
100393view19:26, 31 October 2018ReactomeTeamreactome version 64
99941view16:10, 31 October 2018ReactomeTeamreactome version 63
99497view14:44, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99146view12:41, 31 October 2018ReactomeTeamreactome version 62
94010view13:51, 16 August 2017ReactomeTeamreactome version 61
93733view13:24, 16 August 2017ReactomeTeamreactome version 61
93731view12:48, 16 August 2017ReactomeTeamreactome version 61
93629view11:29, 9 August 2017ReactomeTeamreactome version 61
86740view09:25, 11 July 2016ReactomeTeamreactome version 56
83276view10:37, 18 November 2015ReactomeTeamVersion54
81395view12:55, 21 August 2015ReactomeTeamVersion53
76864view08:13, 17 July 2014ReactomeTeamFixed remaining interactions
76569view11:55, 16 July 2014ReactomeTeamFixed remaining interactions
75902view09:55, 11 June 2014ReactomeTeamRe-fixing comment source
75603view10:45, 10 June 2014ReactomeTeamReactome 48 Update
74958view13:48, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74602view08:39, 30 April 2014ReactomeTeamReactome46
69045view17:53, 8 July 2013MaintBotUpdated to 2013 gpml schema
45208view17:19, 7 October 2011KhanspersOntology Term : 'VEGF signaling pathways' added !
42135view21:59, 4 March 2011MaintBotAutomatic update
39945view05:57, 21 January 2011MaintBotNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
FIGF ProteinO43915 (Uniprot-TrEMBL)
FLT1 ProteinP17948 (Uniprot-TrEMBL)
FLT1ProteinP17948 (Uniprot-TrEMBL)
FLT4 ProteinP35916 (Uniprot-TrEMBL)
FLT4ProteinP35916 (Uniprot-TrEMBL)
KDR ProteinP35968 (Uniprot-TrEMBL)
KDRProteinP35968 (Uniprot-TrEMBL)
NRP1 VEGFR2 dimerComplexREACT_12681 (Reactome)
NRP1 ProteinO14786 (Uniprot-TrEMBL)
NRP1ProteinO14786 (Uniprot-TrEMBL)
NRP2 VEGFR1 dimerComplexREACT_13266 (Reactome)
NRP2 ProteinO60462 (Uniprot-TrEMBL)
NRP2ProteinO60462 (Uniprot-TrEMBL)
PGF ProteinP49763 (Uniprot-TrEMBL)
VEGF dimerComplexREACT_12721 (Reactome)
VEGF-A,C,D dimersComplexREACT_12894 (Reactome)
VEGFA ProteinP15692 (Uniprot-TrEMBL)
VEGFA, VEGFB, PGF dimersComplexREACT_12921 (Reactome)
VEGFB ProteinP49765 (Uniprot-TrEMBL)
VEGFC ProteinP49767 (Uniprot-TrEMBL)
VEGFC,VEGFD dimersComplexREACT_12875 (Reactome)
VEGFR1 dimer VEGFA, VEGFB, PGF dimersComplexREACT_12847 (Reactome)
VEGFR2 VEGFA,C,DComplexREACT_13060 (Reactome)
VEGFR3 dimer VEGFC, VEGFD dimersComplexREACT_12751 (Reactome)
VEGFProteinREACT_12955 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
FLT1REACT_12556 (Reactome)
FLT1REACT_12600 (Reactome)
FLT4REACT_12533 (Reactome)
KDRREACT_12440 (Reactome)
KDRREACT_12494 (Reactome)
NRP1REACT_12494 (Reactome)
NRP2REACT_12600 (Reactome)
REACT_12440 (Reactome) VEGFR-2 binds VEGF-A, -C, -D, and -E homodimers. VEGFR-2 is the primary mediator of the physiological effects of VEGF-A in angiogenesis, including microvascular permeability, endothelial cell proliferation, invasion, migration, and survival. In endothelial cells, these effects are mediated via activation of a phospholipase gamma-protein kinase C-Raf-MAPK signaling pathway for proliferation and PI3K and focal adhesion kinase for survival and migration. VEGFR-2 is the important receptor among VEGFR protiens and its activation and signaling may be positively or negatively regulated by co-expression and activation of various factors and other VEGF receptors like VEGFR-1 (Hicklin and Ellis 2005).The regulatory events of this receptor will be annotated in subsequent modules.
REACT_12494 (Reactome) Plasma membrane-associated Neuropilin-1 (NRP1) binds vascular endothelial growth factor (VEGF) family members. NRP1 has three distinct extracellular domains, a1a2, b1b2, and c but lacks a distinct intracellular domain. VEGF165 mediates the formation of complexes containing VEGFR-2 and NRP-1, enhancing VEGF165-receptor binding on the endothelial cell membrane (Soker et al. 2002). The role of heparin, a critical component of NRP-1 interactions with VEGF proteins, will annotated in detail in future.
REACT_12533 (Reactome) VEGFR-3 preferentially binds VEGF-C and -D. Mutations of the VEGFR-3 tyrosine kinase domain are seen in human lymphedema. VEGFR-3 expression has been correlated with transient lymphangiogenesis in wound healing and may modulate VEGFR-2 signaling in maintaining vascular integrity (Hicklin and Ellis 2005).
REACT_12556 (Reactome) VEGFR-1 binds VEGF-A, VEGF-B, and PLGF homodimers. This interaction is required for normal angiogenesis and hematopoiesis, although many of the detailed molecular steps from binding to these physiological consequences remain unclear (Hickins and Ellis, 2005). VEGFR-1 is made up of 1338 aa and has three regions: an extracellular region consisting of 7 immunoglobin-like domains, a transmembrane (TM) domain and a cytosolic tyrosine kinase (TK) domain. An alternatively spliced form, soluble VEGFR-1 (sVEGFR1), also binds VEGF proteins and may serve in the body to down-regulate VEGF activation of membrane-bound receptors. Overexpression of sVEGFR1 (VEGF121) is associated with preeclampsia, a major disorder of pregnancy (Shibuya and Claesson-Welsh 2006; Levine et al. 2004).
REACT_12588 (Reactome) VEGF proteins bind their receptors as homodimers. Heterodimers with PLGF and among different VEGF proteins have been observed but have no known function.
REACT_12600 (Reactome) NRP-2 associates with VEGFR-1 on the plasma membrane. As NRP-2 lacks an intracellular domain, this association may be the means by which NRP-2 participates in VEGF-induced signaling. This interaction requires VEGF to bridge between NRP and the receptor.
VEGF-A,C,D dimersREACT_12440 (Reactome)
VEGFA, VEGFB, PGF dimersREACT_12556 (Reactome)
VEGFC,VEGFD dimersREACT_12533 (Reactome)
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