VEGF signaling via VEGFR2 - generic
VEGF family of ligands and receptors is crucial for vascular development and
neovascularization in physiological and pathological processes in both embryo and adult.
VEGFR-2 is a high-affinity receptor for
VEGF-A. Activated VEGFR-2 can
activate p38 MAPK, PI3K reg class
IA/ eNOS/ NO,
PLC-gamma 1/ PKC/
ERK1/2 and PLC-gamma 1/
Ca('2+) cytosol pathways in ECs. This contributes to cell
proliferation, angiogenesis, survival, cytoskeleton remodeling, migration and activation
of vascular permeability in ECs.
Vascular endothelial growth factor family of ligands and receptors is crucial for
vascular development and neovascularization in physiological and pathological processes
in both embryo and adult . 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
VEGFR-2 is a high-affinity receptor for
VEGF-A . Activated
VEGFR-2 can activate PLC-gamma
1 directly or through the c-Src and
TSAD adapter proteins , , . PLC-gamma 1 activation 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+)
cytosol. , , , .
PKC-beta phosphorylates and activates
c-Raf-1 triggering MEK1
(MAP2K1) and MEK2 (MAP2K2)/
ERK1/2 signaling cascade.
ERK1/2 can also be activated through
PKC/ Sphingosine kinase 1
(SPHK1) pathway .
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 , . VEGFR-2 can also activate
Prostaglandin I2 production through the
ERK1/2 pathway contributing to
VEGF-A-induced vascular permeability and angiogenesis in
endothelial cells (ECs) .
DAG is also a physiological activator of
PKC-alpha which can signal through
IKK-alpha and IKK-beta to
I-kB/ NF-kB p50/p65 pathway.
NF-kB p50/p65 together with
c-Jun/c-Fos activate transcription of
CCL2 , .
VEGFR-2 also binds and activates PI3K reg
class IA , followed by activation of PI3K
cat class IA, which then results in an increase in lipid
PtdIns(3,4,5)P3 and activation of PDK
(PDPK1)/ AKT(PKB) pathway.
AKT(PKB) signaling pathway regulates cellular survival by
inhibiting pro-apoptotic pathways and inducing survival of ECs , . PI3K reg class IA through
PtdIns(3,4,5)P3 also activates
Rac1. Rac1 can contribute to
AKT(PKB) phosphorylation likely through the
PAK1-dependent PDK (PDPK1)
activation , .
AKT(PKB) can directly phosphorylate
eNOS leading to nitric oxide production , , . Another mechanism of
eNOS activation involves phosphorylation of
PLC-gamma 1, which leads to increase in intracellular levels
of IP3 and elevation of Ca('2+)
cytosol. Increase in Ca('2+) cytosol
concentration stimulates eNOS to produce nitric oxide
(NO) , .
Ca('2+) cytosol also activates
PKC-alpha, which can directly induce
AKT(PKB)/ eNOS signaling . VEGF-A through
VEGFR-2 also induce upregulation of both
eNOS and iNOS protein levels
supporting the important role of NO in
VEGF-A-mediated ECs function and angiogenesis .
Release of Ca('2+) cytosol also activates
Calcineurin A (catalytic)/
NF-AT2(NFATC1)/ COX-2 (PTGS2)
pathway, which leads to upregulation of COX-2 (PTGS2)
activity and induction of proliferation and angiogenesis of ECs , , , . VEGF-A/
VEGFR-2 signaling upregulates protein expression of
COX-1 (PTGS1) which also contributes to cell proliferation
and angiogenesis in ECs .
VEGF-A-induced stimulation of
VEGFR-2 also results in its association with
Shc and GRB2 and the induction
of Shc/ GRB2 complex formation.
It is possible that Shc then mediates coupling of the
GRB2/ SOS complex, promoting
mitogenic H-Ras/ ERK1/2
signaling in ECs , , .
Activated VEGFR-2 can associate with
Fyn, which forms a complex with
NCK1 and PAK2. This leads to
activation of CDC42/
p38 MAPK pathway. Activation of p38
MAPK triggers phosphorylation of the Actin
cytoskeletal polymerization modulator, HSP27
and subsequent cytoskeleton remodeling , , , , , .
Activated p38alpha (MAPK14) and
ERK1/2 induce GSK3 beta/
Beta-catenin pathway and transcriptional activation of
PLAUR (uPAR) most likely through the transcription factor
TCF7L2 (TCF4). VEGF-A through
VEGFR-2 can also activate PLAU
(UPA), which leads to the activation of the PLAU
(UPA)/ PLAUR (uPAR) system and increase in
vascular permeability of ECs , , , .
Ligand-activated VEGFR-2 associates with
HSP90, which induces phosphorylation of
FAK1 in a RhoA/
ROCK1-dependent manner, leading to the recruitment of
Vinculin and Paxillin. This
leads to assembly of focal adhesions and stress fiber formation and subsequent migration
of ECs , . VEGFR-2 also
associates with c-Src and SHB
adapter proteins, which directly activate FAK1 signaling
VEGF-A triggers a synergistic interaction between the
VEGFR-2 and the clustered alpha-V/beta-3
integrin. The interaction between VEGFR-2 and
alpha-V/beta-3 integrin is required for full phosphorylation
of VEGFR-2 and drives the activation of
FAK1 and p38 MAPK pathways and
migratory activity of ECs .
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