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, 3.1.4.11, IKK-gamma, SP3, NF-kB, I-kB, SP1, IP3, ERK1/2, 2.7.1.137, IKK-alpha, VCAM1, PKC-alpha, Brca1, p120GAP, ICAM1, MEK1(MAP2K1), VEGF-A, PKC-beta, MEK2(MAP2K2), IKK-beta, c-Jun, IKK (cat)

Description

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].

References:

  1. Zachary I, Gliki G
    Signaling transduction mechanisms mediating biological actions of the vascular endothelial growth factor family. Cardiovascular research 2001 Feb 16;49(3):568-81
  2. Cross MJ, Dixelius J, Matsumoto T, Claesson-Welsh L
    VEGF-receptor signal transduction. Trends in biochemical sciences 2003 Sep;28(9):488-94
  3. Shu X, Wu W, Mosteller RD, Broek D
    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
  4. Takahashi T, Yamaguchi S, Chida K, Shibuya M
    A single autophosphorylation site on KDR/Flk-1 is essential for VEGF-A-dependent activation of PLC-gamma and DNA synthesis in vascular endothelial cells. The EMBO journal 2001 Jun 1;20(11):2768-78
  5. Marumo T, Schini-Kerth VB, Busse R
    Vascular endothelial growth factor activates nuclear factor-kappaB and induces monocyte chemoattractant protein-1 in bovine retinal endothelial cells. Diabetes 1999 May;48(5):1131-7
  6. Kim I, Moon SO, Kim SH, Kim HJ, Koh YS, Koh GY
    Vascular endothelial growth factor expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin through nuclear factor-kappa B activation in endothelial cells. The Journal of biological chemistry 2001 Mar 9;276(10):7614-20
  7. Dayanir V, Meyer RD, Lashkari K, Rahimi N
    Identification of tyrosine residues in vascular endothelial growth factor receptor-2/FLK-1 involved in activation of phosphatidylinositol 3-kinase and cell proliferation. The Journal of biological chemistry 2001 May 25;276(21):17686-92
  8. Safe S
    Transcriptional activation of genes by 17 beta-estradiol through estrogen receptor-Sp1 interactions. Vitamins and hormones 2001;62:231-52
  9. Stoner M, Wormke M, Saville B, Samudio I, Qin C, Abdelrahim M, Safe S
    Estrogen regulation of vascular endothelial growth factor gene expression in ZR-75 breast cancer cells through interaction of estrogen receptor alpha and SP proteins. Oncogene 2004 Feb 5;23(5):1052-63