Pathway maps

Development_VEGF signaling and activation
Development_VEGF signaling and activation

Object List (links open in MetaCore):

PI3K reg class IA, SPHK1, PtdIns(3,4,5)P3, PI3K cat class IA, PKC, PtdIns(4,5)P2, 2.7.1.-, c-Src, VEGFR-2, PLC-gamma 1, AKT(PKB), Neurofibromin, c-Raf-1, c-Fos, E-selectin, DAG, ESR1 (nuclear), sphingosine, c-Jun/c-Fos, Sphingosine 1-phosphate, H-Ras,, IKK-gamma, SP3, NF-kB, I-kB, SP1, IP3, ERK1/2,, IKK-alpha, VCAM1, PKC-alpha, Brca1, p120GAP, ICAM1, MEK1(MAP2K1), VEGF-A, PKC-beta, MEK2(MAP2K2), IKK-beta, c-Jun, IKK (cat)


VEGF signaling and activation

The 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 that currently consists of five members: VEGF-A, -B, -C, -D, and placenta growth factor PLGF.

VEGFR-2 is a high-affinity receptor for VEGF-A [1]. The activated VEGFR-2 binds Phospholipase C gamma 1 ( PLC-gamma 1 ) That leads to the phosphorylation and activation of this protein and 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 the 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) )/ Mitogen-activated protein kinase kinase 2( MEK2 (MAP2K2) )/ Mitogen-activated protein kinase 3/1 ( Erk (MAPK1/3) ) signaling cascade. Erk ( MAPK1/3) can also be activated through PKC/ Sphingosine kinase 1 ( SPK1 ) pathway [3]. SPK1 is an enzyme which catalyses Spingosine 1 phosphate formation from Sphingosine. Decrease of sphingosine concentration and increase of sphingosine 1-phosphate leads to activation of V-Ha-ras Harvey rat sarcoma viral oncogene homolog ( H-Ras ), apparently through inhibition of Neurofibromin and RAS p21 protein activator 1 ( p120GAP ). H-Ras in turn binds to and activates c-Raf-1 leading to Erk (MAPK1/3) activation. Activated Erk (MAPK1/3) activates by phosphorylation Jun oncogene( c-Jun ). The latter one forms a complex with V-fos FBJ murine osteosarcoma viral oncogene homolog ( c-Fos ) protein leading to DNA synthesis and cell proliferation [4].

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 I-kB/ NF-kB pathway. [5], [6]. NF-kB activates transcription of Intercellular adhesion molecule 1 ( ICAM1 ), Vascular cell adhesion molecule 1 ( VCAM1 ) and E-selectin [6].

VEGFR-2 also binds and activates Phosphoinositide-3-kinase regulatory subunit ( PI3K reg class IA ) [7] followed by the activation of catalytic subunits of PI3K - PI3K cat class IA, which, in turn, results in an increase in lipid Phosphatidylinositol (3,4,5) ( PtdIns(3,4,5)P3 ) and activation of V-akt murine thymoma viral oncogene homolog 1 AKT(PKB). The AKT(PKB) signaling pathway regulates cellular survival by inhibiting pro-apoptotic pathways [2].

Brca1 represses the activity of VEGF-A via ESR1 and SP1 and SP3 [8], [9].


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    Signaling transduction mechanisms mediating biological actions of the vascular endothelial growth factor family. Cardiovascular research 2001 Feb 16;49(3):568-81
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    VEGF-receptor signal transduction. Trends in biochemical sciences 2003 Sep;28(9):488-94
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    Sphingosine kinase mediates vascular endothelial growth factor-induced activation of ras and mitogen-activated protein kinases. Molecular and cellular biology 2002 Nov;22(22):7758-68
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