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:
- 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
- Cross MJ, Dixelius J, Matsumoto T, Claesson-Welsh L
VEGF-receptor signal transduction.
Trends in biochemical sciences 2003 Sep;28(9):488-94
- 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
- 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
- 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
- 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
- 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
- Safe S
Transcriptional activation of genes by 17 beta-estradiol through estrogen receptor-Sp1 interactions.
Vitamins and hormones 2001;62:231-52
- 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
