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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].