Gene Report

Basic Information

Approved Symbol	VEGFA
Approved Name	vascular endothelial growth factor A
Previous Symbol	VEGF
Previous Name	vascular endothelial growth factor
Symbol Alias	VEGF-A, VPF
Location	6p12
Position	chr6:43737946-43754224 (+)
External Links	Entrez Gene: 7422 Ensembl: ENSG00000112715 UCSC: uc003owh.3 HGNC ID: 12680
No. of Studies (Positive/Negative)	1(1/0)
Type	Literature-origin

Positive relationships between VEGFA and MDD (count: 1)

Name in Literature	Reference	Research Type	Statistical Result	Relation Description
VEGF	Iga, 2007	patients and normal controls		The VEGF mRNA levels in the peripheral leukocytes from drug-...... The VEGF mRNA levels in the peripheral leukocytes from drug-naive MDD patients were significantly higher than those from the control subjects More...

Positive relationships between VEGFA and other components at different levels (count: 0)

Positive relationship network of VEGFA in MK4MDD

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Note:
1. The different color of the nodes denotes the level of the nodes.

Genetic/Epigenetic Locus	Protein and Other Molecule	Cell and Molecular Pathway	Neural System	Cognition and Behavior	Symptoms and Signs	Environment	MDD

2. Besides the component related relationships from literature, gene mapped protein and protein mapped gene are also shown in the network. If the mapped gene or protein is not from literature, square node would be used instead of Circle node. Accordingly, the relationship is marked with dot line.
2. User can drag the nodes to rearrange the layout of the network. Click the node will enter the report page of the node. Right-click will show also the menus to link to the report page of the node and remove the node and related edges. Hover the node will show the level of the node and hover the edge will show the evidence/description of the edge.
3. The network is generated using Cytoscape Web

Negative relationships between VEGFA and MDD (count: 0)

Negative relationships between VEGFA and other components at different levels (count: 0)

VEGFA related SNPs in MK4MDD (count: 0)

VEGFA related proteins in MK4MDD (count: 1)

Approved Name	UniportKB	No. of Studies (Positive/Negative)	Source
Vascular endothelial growth factor A	P15692	0(0/0)	Gene mapped

VEGFA related GO terms (count: 113)

ID	Name	Type	Evidence
Gene mapped GO terms
GO:0042803	protein homodimerization activity	molecular function	ISS
GO:0043117	positive regulation of vascular permeability	biological process	IDA[16109918]
GO:0031077	post-embryonic camera-type eye development	biological process	ISS
GO:0000122	negative regulation of transcription from RNA polymerase II promoter	biological process	IDA[18093989]
GO:0048469	cell maturation	biological process	ISS
GO:0051894	positive regulation of focal adhesion assembly	biological process	IDA[16489009]
GO:0050679	positive regulation of epithelial cell proliferation	biological process	ISS
GO:0032147	activation of protein kinase activity	biological process	IDA[18059339]
GO:0048754	branching morphogenesis of a tube	biological process	ISS
GO:1900086	positive regulation of peptidyl-tyrosine autophosphorylation	biological process	IDA
GO:0035924	cellular response to vascular endothelial growth factor stimulus	biological process	IDA[18440775]
GO:0005578	proteinaceous extracellular matrix	cellular component	NAS[14570917]
GO:0002092	positive regulation of receptor internalization	biological process	IDA
GO:0005125	cytokine activity	molecular function	IDA[18440775]; ISS
GO:0008201	heparin binding	molecular function	IDA[15001987]; IMP[14570917]
GO:0030855	epithelial cell differentiation	biological process	ISS
GO:0030168	platelet activation	biological process	TAS
GO:0050840	extracellular matrix binding	molecular function	IC[14570917]
GO:0043406	positive regulation of MAP kinase activity	biological process	IDA[18440775]
GO:0043183	vascular endothelial growth factor receptor 1 binding	molecular function	IPI[1312256]
GO:0038091	positive regulation of cell proliferation by VEGF-activated platelet derived growth factor receptor signaling pathway	biological process	IDA[17470632]
GO:0060319	primitive erythrocyte differentiation	biological process	ISS
GO:0008284	positive regulation of cell proliferation	biological process	IDA[7929439]
GO:0051781	positive regulation of cell division	biological process	IEA
GO:0043536	positive regulation of blood vessel endothelial cell migration	biological process	IDA
GO:0010595	positive regulation of endothelial cell migration	biological process	IDA
GO:0060754	positive regulation of mast cell chemotaxis	biological process	IDA[19275959]
GO:0040007	growth	biological process	ISS
GO:0001569	patterning of blood vessels	biological process	ISS
GO:0016020	membrane	cellular component	IEA
GO:0043129	surfactant homeostasis	biological process	ISS
GO:0048018	receptor agonist activity	molecular function	IPI
GO:0005161	platelet-derived growth factor receptor binding	molecular function	IPI[17470632]
GO:0030324	lung development	biological process	ISS
GO:0002052	positive regulation of neuroblast proliferation	biological process	ISS
GO:0042462	eye photoreceptor cell development	biological process	ISS
GO:0031954	positive regulation of protein autophosphorylation	biological process	IDA
GO:0001822	kidney development	biological process	ISS
GO:0043184	vascular endothelial growth factor receptor 2 binding	molecular function	IPI
GO:0045785	positive regulation of cell adhesion	biological process	IDA[19674970]
GO:0090050	positive regulation of cell migration involved in sprouting angiogenesis	biological process	IDA
GO:0031334	positive regulation of protein complex assembly	biological process	IDA[16489009]
GO:0010628	positive regulation of gene expression	biological process	IDA[18386220]
GO:0090037	positive regulation of protein kinase C signaling cascade	biological process	IDA[18059339]
GO:0006357	regulation of transcription from RNA polymerase II promoter	biological process	IMP[18093989]
GO:0043066	negative regulation of apoptotic process	biological process	IMP[10066377]
GO:0005576	extracellular region	cellular component	TAS
GO:0005615	extracellular space	cellular component	IDA[9202027]; ISS
GO:0008083	growth factor activity	molecular function	IDA; ISS
GO:0002042	cell migration involved in sprouting angiogenesis	biological process	IDA
GO:0007596	blood coagulation	biological process	TAS
GO:0001541	ovarian follicle development	biological process	ISS
GO:0005515	protein binding	molecular function	IPI
GO:0008360	regulation of cell shape	biological process	IDA[10527820]
GO:0050927	positive regulation of positive chemotaxis	biological process	IDA[12744932]
GO:0050930	induction of positive chemotaxis	biological process	IDA[19275959]; NAS[12744932]
GO:0045766	positive regulation of angiogenesis	biological process	IDA; IMP[18275976]
GO:0001570	vasculogenesis	biological process	TAS[15015550]
GO:0051272	positive regulation of cellular component movement	biological process	IDA[10527820]
GO:0007595	lactation	biological process	ISS
GO:0001701	in utero embryonic development	biological process	ISS
GO:0031093	platelet alpha granule lumen	cellular component	TAS
GO:0002575	basophil chemotaxis	biological process	IDA[17082651]
GO:0001968	fibronectin binding	molecular function	IDA[14570917]
GO:0043498	cell surface binding	molecular function	IDA[17470632]
GO:0045944	positive regulation of transcription from RNA polymerase II promoter	biological process	IDA[18093989]; IMP[18093989]
GO:0001525	angiogenesis	biological process	IDA[11427521]
GO:0002053	positive regulation of mesenchymal cell proliferation	biological process	ISS
GO:0048010	vascular endothelial growth factor receptor signaling pathway	biological process	IDA; TAS
GO:0071542	dopaminergic neuron differentiation	biological process	ISS
GO:0032793	positive regulation of CREB transcription factor activity	biological process	IDA
GO:0010740	positive regulation of intracellular protein kinase cascade	biological process	IDA
GO:0005172	vascular endothelial growth factor receptor binding	molecular function	IPI[10471394]
GO:0002576	platelet degranulation	biological process	TAS
GO:0030949	positive regulation of vascular endothelial growth factor receptor signaling pathway	biological process	IDA[7929439]
GO:0003169	coronary vein morphogenesis	biological process	ISS
GO:0042802	identical protein binding	molecular function	IPI
GO:0048739	cardiac muscle fiber development	biological process	ISS
GO:0071456	cellular response to hypoxia	biological process	IDA[10575000]; TAS
GO:0048593	camera-type eye morphogenesis	biological process	ISS
GO:0007498	mesoderm development	biological process	ISS
GO:0009986	cell surface	cellular component	IDA[17470632]
GO:1901727	positive regulation of histone deacetylase activity	biological process	IDA
GO:0005737	cytoplasm	cellular component	IDA[17082651]
GO:0060749	mammary gland alveolus development	biological process	ISS
GO:0001938	positive regulation of endothelial cell proliferation	biological process	IDA[10022831]; ISS
GO:0007399	nervous system development	biological process	TAS[15351965]
GO:0048844	artery morphogenesis	biological process	ISS
GO:0061419	positive regulation of transcription from RNA polymerase II promoter in response to hypoxia	biological process	IMP[19652095]
GO:0033138	positive regulation of peptidyl-serine phosphorylation	biological process	IDA
GO:1900745	positive regulation of p38MAPK cascade	biological process	IDA[18386220]
GO:0090190	positive regulation of branching involved in ureteric bud morphogenesis	biological process	ISS
GO:0050731	positive regulation of peptidyl-tyrosine phosphorylation	biological process	IDA[10022831]
GO:0042056	chemoattractant activity	molecular function	IDA
GO:0030225	macrophage differentiation	biological process	IDA
GO:0003007	heart morphogenesis	biological process	ISS
GO:0060948	cardiac vascular smooth muscle cell development	biological process	ISS
GO:0030141	secretory granule	cellular component	IDA[17082651]
GO:0001934	positive regulation of protein phosphorylation	biological process	IDA[18386220]
GO:0030335	positive regulation of cell migration	biological process	IDA[7929439]
GO:0030224	monocyte differentiation	biological process	IDA
GO:0003151	outflow tract morphogenesis	biological process	ISS
GO:0043154	negative regulation of cysteine-type endopeptidase activity involved in apoptotic process	biological process	IDA[18386220]
GO:0046982	protein heterodimerization activity	molecular function	IDA[8702615]
GO:0001666	response to hypoxia	biological process	IDA[16490744]
GO:0036303	lymph vessel morphogenesis	biological process	ISS
GO:0002687	positive regulation of leukocyte migration	biological process	TAS[1312256]
GO:0060982	coronary artery morphogenesis	biological process	ISS
GO:0033554	cellular response to stress	biological process	TAS
GO:0061418	regulation of transcription from RNA polymerase II promoter in response to hypoxia	biological process	TAS
GO:0035767	endothelial cell chemotaxis	biological process	IDA[18440775]
GO:0050918	positive chemotaxis	biological process	IDA[19275959]
GO:0038033	positive regulation of endothelial cell chemotaxis by VEGF-activated vascular endothelial growth factor receptor signaling pathway	biological process	IDA

VEGFA related KEGG pathways (count: 8)

ID	Name	Brief Description	Full Description
Literature-origin KEGG pathway
hsa04510	focal adhesion	Focal adhesion	Cell-matrix adhesions play essential roles in important biol...... Cell-matrix adhesions play essential roles in important biological processes including cell motility, cell proliferation, cell differentiation, regulation of gene expression and cell survival. At the cell-extracellular matrix contact points, specialized structures are formed and termed focal adhesions, where bundles of actin filaments are anchored to transmembrane receptors of the integrin family through a multi-molecular complex of junctional plaque proteins. Some of the constituents of focal adhesions participate in the structural link between membrane receptors and the actin cytoskeleton, while others are signalling molecules, including different protein kinases and phosphatases, their substrates, and various adapter proteins. Integrin signaling is dependent upon the non-receptor tyrosine kinase activities of the FAK and src proteins as well as the adaptor protein functions of FAK, src and Shc to initiate downstream signaling events. These signalling events culminate in reorganization of the actin cytoskeleton; a prerequisite for changes in cell shape and motility, and gene expression. Similar morphological alterations and modulation of gene expression are initiated by the binding of growth factors to their respective receptors, emphasizing the considerable crosstalk between adhesion- and growth factor-mediated signalling. More...
hsa04150	mtor signaling_pathway	mTOR signaling pathway

ID	Name	Brief Description	Full Description
Gene mapped KEGG pathways
hsa04060	cytokine cytokine_receptor_interaction	Cytokine-cytokine receptor interaction	Cytokines are soluble extracellular proteins or glycoprotein...... Cytokines are soluble extracellular proteins or glycoproteins that are crucial intercellular regulators and mobilizers of cells engaged in innate as well as adaptive inflammatory host defenses, cell growth, differentiation, cell death, angiogenesis, and development and repair processes aimed at the restoration of homeostasis. Cytokines are released by various cells in the body, usually in response to an activating stimulus, and they induce responses through binding to specific receptors on the cell surface of target cells. Cytokines can be grouped by structure into different families and their receptors can likewise be grouped. More...
hsa05219	bladder cancer	Bladder cancer	Bladder cancer arise and progress along two distinctive path...... Bladder cancer arise and progress along two distinctive pathways. The first of these is often preceded by simple and papillary hyperplasia and exhibits a tumour morphology that is low-grade, superficial and papillary. Papillary carcinoma has a tendency to recur locally, but rarely invades and metastasizes. These tumors frequently show a constitutive activation of the receptor tyrosine kinase-Ras pathway, exhibiting activating mutations in the HRAS and fibroblast growth factor receptor 3 (FGFR3) genes. The second tumour pathway is characterized by high-grade muscle-invasive tumours, which either originate from flat carcinoma in situ (CIS)/severe dysplasia or arise de novo. Over half of these tumours show defects in the tumour suppressors p53 and/or the retinoblastoma protein (RB) genes and pathways, and over 50% of these tumours progress to local and distant metastases. Some of the cell cycle-related molecules show evidence of epigenetic modulation through aberrant promoter hypermethylation in invasive bladder cancer. Invasion and metastases are promoted by several factors that alter the tumour microenvironment, including the aberrant expression of E-cadherins (E-cad), matrix metalloproteinases (MMPs), angiogenic factors such as vascular endothelial growth factor (VEGF). More...
hsa05211	renal cell_carcinoma	Renal cell carcinoma	Renal cell carcinoma (RCC) is a heterogenous term comprising...... Renal cell carcinoma (RCC) is a heterogenous term comprising a group of neoplasms of renal origin. There are 4 major histologic subtypes of RCC: conventional (clear cell RCC, 75%), papillary (15%), chromophobic (5%), and collecting duct (2%). Multiple genes are involved in the molecular pathogenesis of RCC. VHL is a tumor suppressor gene responsible for hereditary (von Hippel-Lindau) and sporadic variants of conventional (clear cell) RCC. In the absence of VHL, hypoxia-inducible factor alpha (HIF-alpha) accumulates, leading to production of several growth factors, including vascular endothelial growth factor and platelet-derived growth factor. An oncogene, MET has been found to be mutant in cases of hereditary papillary renal cancer (HPRC), although the incidence of c-MET mutations is low in sporadic papillary RCC. Once activated, MET mediates a number of biological effects including motility, invasion of extracellular matrix, cellular transformation, prevention of apoptosis and metastasis formation. Mutations in the fumarate hydratase (FH) gene cause hereditary leiomyomatosis and renal cancer syndrome (HLRCC) papillary renal tumors, although the incidence of FH mutations in sporadic tumors is unknown. Loss of functional FH leads to accumulation of fumarate in the cell, triggering inhibition of HPH and preventing targeted pVHL-mediated degradation of HIF-alpha. BHD mutations cause the Birt-Hogg-Dube syndrome and its associated chromophobe, hybrid oncocytic, and conventional (clear cell) RCC. The incidence of BHD mutations in sporadic renal tumors is not known. More...
hsa05212	pancreatic cancer	Pancreatic cancer	Normal duct epithelium progresses to infiltrating cancer thr...... Normal duct epithelium progresses to infiltrating cancer through a series of histologically defined precursors (PanINs). The overexpression of HER-2/neu and activating point mutations in the K-ras gene occur early, inactivation of the p16 gene at an intermediate stage, and the inactivation of p53, SMAD4, and BRCA2 occur relatively late. Activated K-ras engages multiple effector pathways. Although EGF receptors are conventionally regarded as upstream activators of RAS proteins, they can also act as RAS signal transducers via RAS-induced autocrine activation of the EGFR family ligands. Pancreatic ductal adenocarcinoma (PDA) show elevated expression of EGF receptors (e.g. HER2/neu) and their ligands (e.g.TGF-alpha) consistent with the presence of this autocrine loop. Moreover, PDA shows extensive genomic instability and aneuploidy. Telomere attrition and mutations in p53 and BRCA2 are likely to contribute to these phenotypes. Inactivation of the SMAD4 tumour suppressor gene leads to loss of the inhibitory influence of the transforming growth factor-beta signalling pathway. More...
hsa04370	vegf signaling_pathway	VEGF signaling pathway	There is now much evidence that VEGFR-2 is the major mediato...... There is now much evidence that VEGFR-2 is the major mediator of VEGF-driven responses in endothelial cells and it is considered to be a crucial signal transducer in both physiologic and pathologic angiogenesis. The binding of VEGF to VEGFR-2 leads to a cascade of different signaling pathways, resulting in the up-regulation of genes involved in mediating the proliferation and migration of endothelial cells and promoting their survival and vascular permeability. For example, the binding of VEGF to VEGFR-2 leads to dimerization of the receptor, followed by intracellular activation of the PLCgamma;PKC-Raf kinase-MEK-mitogen-activated protein kinase (MAPK) pathway and subsequent initiation of DNA synthesis and cell growth, whereas activation of the phosphatidylinositol 3' -kinase (PI3K)-Akt pathway leads to increased endothelial-cell survival. Activation of PI3K, FAK, and p38 MAPK is implicated in cell migration signaling. More...
hsa05200	pathways in_cancer	Pathways in cancer

VEGFA related BioCarta pathways (count: 3)

ID	Name	Brief Description	Full Description
Gene mapped BioCarta pathways
VEGF_PATHWAY	vegf pathway	VEGF, Hypoxia, and Angiogenesis	Vascular endothelial growth factor (VEGF) plays a key role i...... Vascular endothelial growth factor (VEGF) plays a key role in physiological blood vessel formation and pathological angiogenesis such as tumor growth and ischemic diseases. Hypoxia is a potent inducer of VEGF in vitro. The increase in secreted biologically active VEGF protein from cells exposed to hypoxia is partly because of an increased transcription rate, mediated by binding of hypoxia-inducible factor-1 (HIF1) to a hypoxia responsive element in the 5'-flanking region of the VEGF gene. bHLH-PAS transcription factor that interacts with the Ah receptor nuclear translocator (Arnt), and its predicted amino acid sequence exhibits significant similarity to the hypoxia-inducible factor 1alpha (HIF1a) product. HLF mRNA expression is closely correlated with that of VEGF mRNA.. The high expression level of HLF mRNA in the O2 delivery system of developing embryos and adult organs suggests that in a normoxic state, HLF regulates gene expression of VEGF, various glycolytic enzymes, and others driven by the HRE sequence, and may be involved in development of blood vessels and the tubular system of lung. VEGF expression is dramatically induced by hypoxia due in large part to an increase in the stability of its mRNA. HuR binds with high affinity and specificity to the VRS element that regulates VEGF mRNA stability by hypoxia. In addition, an internal ribosome entry site (IRES) ensures efficient translation of VEGF mRNA even under hypoxia. The VHL tumor suppressor (von Hippel-Lindau) regulates also VEGF expression at a post-transcriptional level. The secreted VEGF is a major angiogenic factor that regulates multiple endothelial cell functions, including mitogenesis. Cellular and circulating levels of VEGF are elevated in hematologic malignancies and are adversely associated with prognosis. Angiogenesis is a very complex, tightly regulated, multistep process, the targeting of which may well prove useful in the creation of novel therapeutic agents. Current approaches being investigated include the inhibition of angiogenesis stimulants (e.g., VEGF), or their receptors, blockade of endothelial cell activation, inhibition of matrix metalloproteinases, and inhibition of tumor vasculature. Preclinical, phase I, and phase II studies of both monoclonal antibodies to VEGF and blockers of the VEGF receptor tyrosine kinase pathway indicate that these agents are safe and offer potential clinical utility in patients with hematologic malignancies. More...
HIF_PATHWAY	hif pathway	Hypoxia-Inducible Factor in the Cardiovascular System	Hypoxia (or low O2 levels) affects various pathologies. Firs...... Hypoxia (or low O2 levels) affects various pathologies. First, tissue ischemia, a variation in O2 tension caused by hypoxia/reoxygenation, can lead to endothelial cell changes. For example, long periods of ischemia result in endothelial changes, such as vascular leakage, resulting in varicose veins. In more severe situations, ischemia can lead to myocardial or cerebral infarction and retinal vessel occlusion. Of interest, HIF-1 is stabilized prior to induction of vascular endothelial growth factor (VEGF) expression during acute ischemia in the human heart. Second, pulmonary hypertension associated with chronic respiratory disorders results from persistent vasoconstriction and vascular remodeling. Third, hypoxic gradients created in enlarging solid tumors trigger expression of genes containing hypoxia response element (HRE)s such as those involved in angiogenesis. This allows subsequent delivery of O2, nutrients, and further tumor growth. Vascular remodeling is an important component to tumorigenesis; without proper blood supply, delivery of oxygen may occur by diffusion, but becomes inefficient in tumors greater than 1 mm in diameter. Short-term hypoxia can also elevate platelet numbers, while prolonged exposure may cause some degree of thrombocytopenia in response to increased levels of erythropoetin (EPO). Another disorder involving inadequate responses to hypoxia is preeclampsia, a pathology of pregnancy thought to be caused by improper differentiation of placental trophoblast cells due to poorly controlled O2 tension or improper hypoxia-inducible factor (HIF)-mediated responses. The primary molecular mechanism of gene activation during hypoxia is through HIF-1. Several genes involved in cellular differentiation are directly or indirectly regulated by hypoxia. These include EPO, LDH-A, ET-1, transferrin, transferrin receptor, VEGF, Flk-1, Flt-1, platelet-derived growth factor- (PDGF-), basic fibroblast growth factor (bFGF), and others genes affecting glycolysis. HIF-1 is a member of the basic helix-loop-helix (bHLH)-PAS family of transcription factors known to induce gene expression by binding to a ~50-bp HRE containing a core 5'-ACGTG-3' sequence. bHLH-PAS proteins heterodimerize to form transcription complexes that regulate O2 homeostasis, circadian rhythms, neurogenesis, and toxin metabolism. Three bHLH-PAS proteins in vertebrates respond to hypoxia: HIF-1 , EPAS (HIF-2 ), and HIF-3. These dimerize with ARNT (aryl hydrocarbon receptor nuclear translocator protein), ARNT-2, or ARNT-3. HIF-1 is ubiquitinated and subsequently degraded in less than 5 minutes under normoxic conditions. Although several candidate O2-sensing molecules have emerged in the literature, the molecular basis of how cells sense O2 levels is poorly characterized. pVHL, the protein product of a tumor-suppressor gene responsible for von Hippel Lindau disease, is implicated in this O2-sensing system by its association with HIF-1 , targeting it for ubiquitin-mediated degradation. Similarly, F-box-containing proteins recognize substrates of the ubiquitin ligases, targeting them for phosphorylation-dependent ubiquitination and proteosomal degradation. In addition to F-boxes, most of these proteins also contain a WD40 or a leucine-rich repeat (LLR) domain that presumably functions as a Ser/Thr binding module. A second family of proteins assisting the ubiquitin ligases share a region designated SOCS-box (originally from the suppressor of cytokine signaling proteins SOCS). Under low O2 (<5% O2) HIF-1 is stabilized leading to the formation of a functional transcription factor complex with ARNT. This complex is the master regulator of O2 homeostasis and induces a network of genes involved in angiogenesis, erythropoiesis, and glucose metabolism. More...
NO1_PATHWAY	no1 pathway	Actions of Nitric Oxide in the Heart	Nitric oxide (NO) has a number of important physiological ac...... Nitric oxide (NO) has a number of important physiological actions in the cardiovascular system. In the heart, NO plays role in keeping the vessels patent via vasodilation and prevention of platelet aggregation. It also plays an important role in regulating the force and rate of contraction. In vivo NO is released by shear stress of ligands that increase intracellular Ca2+ in endothelial cells. The increase intracellular Ca2+ activates nitric oxide synthase III (NOSIII) by promoting the binding of Ca/Calmodulin to the enzyme. NOSIII, which is resident in the Golgi complex, is transported together with caveolin-1 to the caveolae at the plasma membrane via vesicles. Shear stress signals via a potassium channel and the cytoskeleton, which results in tyrosine phosphorylation of specific proteins, activation of phosphatidylinositol 3-kinase, and subsequently in activation of Akt kinase. Akt activation by shear stress but also by VEGF activates NOSIII by serine phosphorylation, which increases the affinity of NOSIII for calmodulin. After agonist binding at the plasma membrane, NOSIII-activating receptors translocate to caveolae. VEGF receptor signals via its tyrosine kinase domain. Furthermore, agonist receptors activate calcium channels of the endoplasmic reticulum (ER) via phospholipase C and inositol 1,4,5-trisphosphate. This calcium flux induces binding of calmodulin to NOSIII, whereas the NOSIII-caveolin-1 interaction is disrupted. At the same time, NOSIII is translocated into the cytosol. On binding of calmodulin, NOSIII generates NO, is enhanced by the interaction with Hsp90. Once activated, NOSIII catabolizes L-arginine to NO, which diffuses out of the cell. NO stimulates guanylate (G-) cyclase and increases cGMP levels. cGMP activates cGMP-dependent protein kinase (PKG), cGMP-inhibited phosphodiesterase (PDEIII), and cGMP-stimulated phosphodiesterase (PDEII). PKG may reduce the force and rate of contraction, possibly by phosphorylating troponin I or by phosphorylating phospholamban. PDEIII is inhibited by the increases in cGMP brought about by NO. This may result in an increase in cAMP and cAMP-dependent protein kinase (PKA). PKA in turn activates Ca2+ channels, countering the effects of PKG. In contrast, cGMP may stimulate PDEII, reduce cAMP levels and PKA activity, and thereby reduce Ca2+ channel activity. Ach, acetylcholine. CAT-1, cationic amino acid transporter. More...

VEGFA related Reactome pathways (count: 5)

ID	Name	Description
Gene mapped Reactome pathways
REACT_604	hemostasis	Two principal mechanisms limit blood loss after vascular inj...... Two principal mechanisms limit blood loss after vascular injury. Initially, platelets are activated, adhere to the site of the injury, and aggregate into a plug that limits blood loss. Proteins and small molecules released from activated platelets stimulate the plug formation process, and fibrinogen from the plasma forms bridges between activated platelets. These events allow the initiation of the clotting cascade, the second mechanism to limit blood loss. Negatively charged phospholipids exposed on cell surfaces at the site of injury and on activated platelets interact with tissue factor, setting off a cascade of reactions leading to generation of fibrin and the formation of an insoluble fibrin clot that strengthens the platelet plug. More...
REACT_318	platelet degranulation	Platelets function as exocytotic cells, secreting a plethora...... Platelets function as exocytotic cells, secreting a plethora of effector molecules at sites of vascular injury. Platelets contain a number of distinguishable storage granules including alpha granules, dense granules and lysosomes. On activation platelets release a variety of proteins, largely from storage granules but also as the result of apparent cell lysis. These act in an autocrine or paracrine fashion to modulate cell signaling. Alpha granules contain mainly polypeptides such as fibrinogen, von Willebrand factor, growth factors and protease inhibitors that that supplement thrombin generation at the site of injury. Dense granules contain small molecules, particularly adenosine diphosphate (ADP), adenosine triphosphate (ATP), serotonin and calcium, all recruit platelets to the site of injury. More...
REACT_12529	signaling by_vegf	In normal development vascular endothelial growth factors. M...... In normal development vascular endothelial growth factors. Molecular features of the VGF signaling cascades are outlined in the figure below. 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. More...
REACT_798	platelet activation	Platelet activation begins with the initial binding of adhes...... Platelet activation begins with the initial binding of adhesive ligands and of the excitatory platelet agonists. Intracellular signaling reactions will then enhance the adhesive and procoagulant properties of tethered platelets or of platelets circulating in the proximity. From the subendothelial adhesive substrates, collagen and possibly vWF are the main inducers of platelet activation. GP VI is the most potent collagen receptor initiating signal generation, an ability derived from its interaction with the FcRI gamma chain. This results in the phosphorylation of the gamma-chain by the non-receptor tyrosine kinases of the Src family. The phosphotyrosine motif is recognized by the SH2 domains of Syk, a tyrosine kinase. This association activates the Syk enzyme, leading to activation. Four PARs are identified, of which PARs 1 ,3 and 4 are substrates for thrombin. PAR 1 is the predominant thrombin receptor, PAR 3 is minimally expressed and PAR 4 is less responsive to thrombin. Platelets do not store PAR1, due to limited protein synthesis, they are capable of responding to thrombin only once. Platelet activation further results in the scramblase-mediated transport of negatively-charged phospholipids to the platelet surface. These phospholipids provide a catalytic surface (with the charge provided by phosphatidylserine and phosphatidylethanolamine) for the tenase complex (formed by the activated forms of the blood coagulation factors factor VIII and factor I). More...
REACT_20	formation of_platelet_plug	Hemostasis is a physiological response that culminates in th...... Hemostasis is a physiological response that culminates in the arrest of bleeding from an injured vessel. Acute vessel injury results in its constriction to reduce the loss of blood. Under normal conditions vascular endothelium supports vasodilation, inhibits platelet adhesion and activation, suppresses coagulation, enhances fibrin cleavage and is anti-inflammatory in character. Under acute vascular trauma vasoconstrictor mechanisms predominate and the endothelium becomes prothrombotic, procoagulatory and proinflammatory in nature. This is achieved by a reduction of endothelial dilating agents: adenosine, NO and prostacyclin; and the direct action of ADP, serotonin and thromboxane on vascular smooth muscle cells to elicit their contraction. The chief trigger for the change in endothelial function that leads to the formation of haemostatic thrombus is the loss of the endothelial cell barrier between blood and ECM components. Circulating platelets identify and discriminate areas of endothelial lesions; here, they adhere to the exposed sub endothelium. Their interaction with the various thrombogenic substrates and locally generated or released agonists results in platelet activation. This process is described as possessing two stages, firstly, adhesion - the initial tethering to a surface, and secondly aggregation - the platelet-platelet cohesion. More...

VEGFA related interactors from protein-protein interaction data in HPRD (count: 19)

Gene	Interactor	Interactor in MK4MDD?	Experiment Type	PMID
VEGFA	VTN	No	in vitro	11796824
VEGFA	IGFBP7	Yes	in vitro	12407018
VEGFA	YBX1	Yes	in vitro	16198352
VEGFA	CTGF	No	in vivo;yeast 2-hybrid	11744618
VEGFA	KDR	No	in vivo	8621427 , 17318185
VEGFA	TNXB	No	in vitro	11122379
VEGFA	PGF	No	in vitro;in vivo	12796773 , 12086892
VEGFA	FLT1	No	in vitro;in vivo	8621427 , 17051153 , 9393862
VEGFA	CSDA	No	in vitro	16198352
VEGFA	VEGFA	Yes	in vitro;in vivo	10748121 , 8631822 , 9207067
VEGFA	GPC1	No	in vitro;in vivo	10196157
VEGFA	SEMA3F	Yes	in vitro;in vivo	12845630
VEGFA	NRP1	No	in vitro;in vivo	11986311 , 10409677 , 9529250 , 17222790 , 16763549
VEGFA	AKT1	No	in vivo	17318185
VEGFA	EPHB2	No	in vivo	17318185
VEGFA	VEGFB	No	in vivo	8702615
VEGFA	NRP2	No	in vivo	10748121
VEGFA	ADAMTS1	No	in vitro;in vivo	12716911
VEGFA	SPARC	No	in vitro	9792673

Gene Report

Gene mapped GO terms

Literature-origin KEGG pathway

Gene mapped KEGG pathways

Gene mapped BioCarta pathways

Gene mapped Reactome pathways