Map Key
Generic Enzyme
Generic kinase
Protein kinase
Lipid kinase
Generic phosphatase
Protein phosphatase
Lipid phosphatase
Generic phospholipase
Generic protease
RAS - superfamily
G beta/gamma
Regulators (GDI, GAP, GEF)
Generic channel
Ligand-gated channel
Voltage-gated channel
Normal process
Pathological process
Positive effect
Negative effect
Unspecified effect
Technical link
Disrupts in disease
Emerges in disease
Enhances in disease
Weakens in disease
Organsim specific interaction

Generic binding protein
Receptor ligand
Cell membrane glycoprotein
Transcription factor
Inorganic ion
Predicted metabolite or user's structure
Generic receptor
Receptors with enzyme activity

Normal process
Pathological process
Covalent modifications
Transcription regulation
MicroRNA binding
Influence on expression
Unspecified interactions
Pharmacological effect
Toxic effect
Group relation
Complex subunit
Similarity reaction
A complex or a group
Organism specific object

Development VEGF signaling via VEGFR2 - generic cascades

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Development VEGF signaling via VEGFR2 - generic cascades

VEGF signaling via VEGFR2 - generic cascades

Vascular endothelial growth factor ( VEGF ) family of ligands and receptors iscrucial for vascular development and neovascularization in physiological and pathologicalprocesses in both embryo and adult [1]. VEGFs denote a family ofhomodimeric glycoproteins, which currently consists of five members ( VEGF-A, VEGF-B,VEGF-C, VEGF-D, and Placenta growth factor ( PLGF )).

VEGFR-2 is a high-affinity receptor for VEGF-A [1].Activated VEGFR-2 binds Phospholipase C gamma 1 ( PLC-gamma 1 ) leading toits phosphorylation and activation, which results in hydrolysis of the membranePhosphatidylinositol (4,5)-bisphosphate ( PtdIns(4,5)P2 ) and generation of thesecond messengers 1,2-diacylglycerol ( DAG ) and Inositol (1,4,5)-trisphosphate (IP3 ). DAG is a physiological activator of Protein kinase C beta 1 (PKC-beta ), whereas IP3 binds to a specific receptor present on endoplasmicreticulum, resulting in the release of intracellular stored Ca(2+) [2].

PKC-beta phosphorylates and activates V-raf-1 murine leukemia viral oncogenehomolog 1 ( c-Raf-1 ) triggering Mitogen-activated protein kinase kinase 1 (MEK1 (MAP2K1) ) and Mitogen-activated protein kinase kinase 2( MEK2(MAP2K2) )/ Mitogen-activated protein kinase 3/1 ( ERK1/2 ) signalingcascade. ERK1/2 can also be activated through PKC/ Sphingosine kinase 1 (SPHK1 ) pathway [3]. SPHK1 is an enzyme which catalysesSpingosine 1 phosphate formation from Sphingosine. Decrease ofSphingosine concentration and increase of sphingosine 1-phosphate may leadto activation of V-Ha-ras Harvey rat sarcoma viral oncogene homolog ( H-Ras )through inhibition of Neurofibromin and RAS p21 protein activator 1 (p120GAP ). H-Ras in turn binds to and activates c-Raf-1 leading toERK1/2 activation. Activated ERK1/2 activates Jun oncogene ( c-Jun )by phosphorylation. The latter forms a complex with V-fos FBJ murine osteosarcoma viraloncogene homolog ( c-Fos ) protein leading to DNA synthesis and cell proliferation[4].

DAG is also a physiological activator of PKC-alpha which can signalthrough Conserved helix-loop-helix ubiquitous kinase ( IKK-alpha ) and Inhibitorof kappa light polypeptide gene enhancer in B-cells kinase beta ( IKK-beta ) toNuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor (I-kB)/Nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 andV-rel reticuloendotheliosis viral oncogene homolog A ( NF-kB p50/p65 ) pathway.NF-kB p50/p65 together with c-Jun/c-Fos activate transcription of Chemokineligand 2 ( CCL2 ) [5], [6]

VEGFR-2 also binds and activates Phosphoinositide-3-kinase regulatory subunit(PI3K reg class IA ) [7], followed by activation of catalyticsubunits of PI3K - PI3K cat class IA, which, then results in an increase in lipidPhosphatidylinositol 3,4,5-triphosphate ( PtdIns(3,4,5)P3 ) and activation ofV-akt murine thymoma viral oncogene homolog 1 ( AKT(PKB) ).

AKT(PKB) signaling pathway regulates cellular survival by inhibitingpro-apoptotic pathways [2]. AKT(PKB) can directly phosphorylateNitric oxide synthase 3 ( eNOS ) leading to nitric oxide production [8], [9]. Another mechanism of eNOS activation involves V-srcsarcoma viral oncogene homolog ( c-Src ) and PLC-gamma 1: VEGF-Areceptor binding causes c-Src activation with subsequent phosphorylation ofPLC-gamma 1 leading to increases in intracellular levels of IP3 andelevation of intracellular calcium. Increase in intracellular calcium concentrationstimulates Nitric oxide synthase 3 ( eNOS ) to produce nitric oxide [10].