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 embryos, and in adults .
VEGFs belong to a family of homodimeric glycoproteins that contains five members
VEGF-C, VEGF-D, and Placenta
growth factor PLGF). VEGFs bind to three different
VEGF-receptor tyrosine kinases (VEGFR-1,
VEGFR-2 and VEGFR-3). Upon
ligation, VEGF-receptors dimerize, autophosphorylate and, thereby transduce signals that
direct cellular function .
VEGFR-1 is a high-affinity receptor for
VEGF-A, VEGF-B and
PLGF , , . It
is expressed in vascular endothelial and some non-endothelial cells including
haematopoietic stem cells, macrophages and monocytes , .
VEGFR-2 is highly specific towards
VEGF-A . However, it also binds the
processed forms of VEGF-C and
VEGFR-2 is expressed in both vacular endothelial and
lymphatic endothelial cells. Its expression has also been demonstrated in several other
cell types such as megakaryocytes and haematopoietic stem cells.
VEGFR-3 is highly specific towards
VEGF-C and VEGF-D , . It is expressed at high levels in lymphatic endothelial
cells, but also is important for vascular development .
VEGF-receptor function is enhanced by interaction with co-receptors of VEGFs
Neuropilin-1 and Neuropilin-2
, , . VEGF-A,
VEGF-B and PLGF bind to
Neuropilin-1, whereas VEGF-A,
VEGF-C and PLGF bind to
Neuropilin-2 , .
Neuropilin-1 stabilizes the
VEGFR-2 complex with VEGF-A
, , whereas Neuropilin-2
might be required for stabilizing the complex of
VEGFR-3 with its ligands .
L1 cell adhesion molecule (L1CAM) and
VEGF-A bind to alpha-V/beta-3
integrin and to VEGFR-2 to
induce endothelial cell adhesion, migration, and survival , .
Extracellular matrix protein Fibronectin binds to
and VEGFR-3 and induces association of the
alpha-5/beta-1 integrin with
VEGFR-3. Both Fibronectin and
VEGF-A bind to VEGFR-3
and selectively promote the growth of
lymphatic endothelial cells .
VEGFR-1 binds to Src homology 2 domain containing
transforming protein (Shc) and Growth factor receptor bound
2 (GRB2). VEGFR-1
also phosphorylates Phospholipase C gamma
(PLC-gamma) , , . VEGFR-1 also can interact with the regulatory
subunit of Phosphatidylinositol 3-kinase (PI3K reg class 1A)
VEGFR-2 is considered to be a major mediator of several
physiological and pathological effects of VEGF-A on
endothelial cells. The activated VEGFR-2 phosphorylates and
activates PLC-gamma, which in turn results in hydrolysis of
the membrane Phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) and generation of the
second messengers 1,2-Diacylglycerol
(IP3). DAG is a
physiological activator of conventional isoforms of Protein kinase C, such as
PKC-alpha, whereas binds to a specific present on the
endoplasmic reticulum (IP3 receptor), resulting in the
release of intracellular stored Ca(2+) .
Activation of ERKs by VRGFR-2 proceeds via a major
pathway that involves association with the adapter proteins
Shc and GRB2, subsequent
stimulation of the guanine nucleotide exchange factor, Son
of sevenless proteins (SOS) and activation of the v-Ha-ras
Harvey rat sarcoma viral oncogene homolog (H-Ras).
H-Ras in turn activates v-Raf-1 murine leukemia viral
oncogene homolog 1 (c-Raf-1)/ Mitogen-activated protein
kinase kinase 1 and 2 (MEK1
and MEK2)/ Mitogen-activated protein kinases
1 and 3 (ERK1/2) cascade, resulting in cell proliferation
VEGFR-2 also binds and activates PI3K reg
class 1A  followed by the activation of the catalytic
subunits of PI3K (PI3K cat class
1A). This results in increase in the lipid Phosphatidylinositol
3,4,5-trisphosphate (PtdIns(3,4,5)P3) and in activation of
the v-AKT murine thymoma viral oncogene homolog (AKT).
AKT-signaling pathway regulates cellular survival by inhibiting pro-apoptotic pathways
The activated VEGFR-3 phosphorylates adapter proteins
Shc and GRB2, and
Shc/GRB2 protein complex can
mediate the signal for lymphatic endothelial cell growth , . The activation of the classical ERK1/2 pathway by
VEGFR-3 is considered to be independent of
H-Ras. Incidentally, PLC-gamma/
PKC-alpha-dependent activation of the ERK1/2
cascade has indeed been reported .
VEGFR-3 activation also leads to induction of
PI3K and stimulation of AKT.
AKT signaling is important for lymphatic and blood
endothelial cell survival .
It is suggested that VEGFR-1 has a dual function in
angiogenesis where it plays negative and positive roles depending on the
VEGFR-1 possesses weak kinase activity that is about 10
times lower than that of VEGFR-2 . However,
VEGFR-1 is capable of transducing signals in endothelial
cells ,  as well as monocytes and macrophages , , , .
VEGFR-1 (or its soluble form
sVEGFR-1) , 
is possibly a "decoy" receptor that sequesters VEGF-A and
thus renders it less available to the functional VEGFR-2
. VEGFR-1 also can directly
bind to Neuropilin-1, thus
competing with VEGF-A. Such inactivated
Neuropilin-1 is unable to interact with
On the other hand, binding of PLGF to
VEGFR-1 in endothelial cells leads to displacement of
VEGF-A from VEGFR-1. As a
result, increased amounts of VEGF-A are available to bind to
the mitogenic response-inducing receptor VEGFR-2 . Moreover, activation of VEGFR-1 by
PLGF results in intermolecular transphosphorylation of
VEGFR-2, and thereby amplification of the angiogenesis
through VEGFR-2 .
The signal-transduction capacity of VEGFR-3 is directly
enhanced by heterodimeric-complex formation with VEGFR-2 in
primary human endothelial cells expressing both receptors .
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