Pathway Map Details

Development_VEGF signaling via VEGFR2 - generic cascades

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Ca('2+) cytosol, PI3K reg class IA, SPHK1, MEK2 (MAP2K2), PtdIns(3,4,5)P3, PKC-alpha, PI3K cat class IA, PKC, PtdIns(4,5)P2, Ca('2+) = Ca('2+), 2.7.1.-, NO, c-Src, VEGFR-2, PLC-gamma 1, AKT(PKB), Neurofibromin, MEK1 (MAP2K1), c-Raf-1, IKK-beta, (L)-Arginine (cytosol), eNOS, DAG, sphingosine, Sphingosine 1-phosphate, H-Ras, IKK-alpha,, IKK-gamma, (L)-Citrulline cytosol, Ca('2+) endoplasmic reticulum lumen, I-kB, NF-kB p50/p65, IP3, ERK1/2,, CCL2, c-Jun, p120GAP, PKC-beta, IP3 receptor, VEGF-A, c-Jun/c-Fos,, IKK (cat)


VEGF signaling via VEGFR2 - generic cascades

Vascular endothelial growth factor ( VEGF ) family of ligands and receptors is crucial for vascular development and neovascularization in physiological and pathological processes in both embryo and adult [1]. VEGFs denote a family of homodimeric 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 to its phosphorylation and activation, which results in hydrolysis of the membrane Phosphatidylinositol (4,5)-bisphosphate ( PtdIns(4,5)P2 ) and generation of the second 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 endoplasmic reticulum, resulting in the release of intracellular stored Ca(2+) [2].

PKC-beta phosphorylates and activates V-raf-1 murine leukemia viral oncogene homolog 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 ) signaling cascade. ERK1/2 can also be activated through PKC/ Sphingosine kinase 1 ( SPHK1 ) pathway [3]. SPHK1 is an enzyme which catalyses Spingosine 1 phosphate formation from Sphingosine. Decrease of Sphingosine concentration and increase of sphingosine 1-phosphate may lead to 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 to ERK1/2 activation. Activated ERK1/2 activates Jun oncogene ( c-Jun ) by phosphorylation. The latter forms a complex with V-fos FBJ murine osteosarcoma viral oncogene homolog ( c-Fos ) protein leading to DNA synthesis and cell proliferation [4], [5].

DAG is also a physiological activator of PKC-alpha which can signal through Conserved helix-loop-helix ubiquitous kinase ( IKK-alpha ) and Inhibitor of kappa light polypeptide gene enhancer in B-cells kinase beta ( IKK-beta ) to Nuclear 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 and V-rel reticuloendotheliosis viral oncogene homolog A ( NF-kB p50/p65 ) pathway. NF-kB p50/p65 together with c-Jun/c-Fos activate transcription of Chemokine ligand 2 ( CCL2 ) [6], [7]

VEGFR-2 also binds and activates Phosphoinositide-3-kinase regulatory subunit (PI3K reg class IA ) [8], followed by activation of catalytic subunits of PI3K - PI3K cat class IA, which, then results in an increase in lipid Phosphatidylinositol 3,4,5-triphosphate ( PtdIns(3,4,5)P3 ) and activation of V-akt murine thymoma viral oncogene homolog 1 ( AKT(PKB) ).

AKT(PKB) signaling pathway regulates cellular survival by inhibiting pro-apoptotic pathways [2]. AKT(PKB) can directly phosphorylate Nitric oxide synthase 3 ( eNOS ) leading to nitric oxide production [9], [10]. Another mechanism of eNOS activation involves V-src sarcoma viral oncogene homolog ( c-Src ) and PLC-gamma 1: VEGF-A receptor binding causes c-Src activation with subsequent phosphorylation of PLC-gamma 1 leading to increases in intracellular levels of IP3 and elevation of intracellular calcium. Increase in intracellular calcium concentration stimulates Nitric oxide synthase 3 ( eNOS ) to produce nitric oxide [11].


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