VEGF-B, MEK1, Vitronectin, PtdIns(4,5)P2, c-Raf-1, IP3, PLC-gamma, PI3K cat class IA, VEGFR-1, PKC-alpha, IP3 receptor, VEGF-D, VEGF-C, Neuropilin-1, Neuropilin-2, 22.214.171.124, c-Jun, Fibronectin, Shc, L1CAM, H-Ras, VEGF-A, SOS, PI3K reg class IA, PLGF, VEGFR-3, Ca(2+) endoplasmic reticulum, 126.96.36.199, None, GRB2, alpha-5/beta-1 integrin, AKT, PtdIns(3,4,5)P3, ERK1/2, c-Fos, MEK2, VEGFR-2, DAG, c-Jun/c-Fos, alpha-V/beta-3 integrin, Ca(2+) cytosol
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-A, VEGF-B, 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 VEGF-D . 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-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 .
Extracellular matrix protein Fibronectin binds to alpha-5/beta-1 integrin 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 ( DAG ) and Inositol (1,4,5)-trisphosphate ( 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 circumstances.
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 VEGFR-2 .
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 .