Development VEGF signaling and activation
VEGF signaling and activation
The vascular endothelial growth factor (VEGF) family of ligands and receptors iscrucial for vascular development and neovascularization in physiological and pathologicalprocesses in both embryo and adult [1]. VEGFs denote a family of homodimericglycoproteins that currently consists of five members: VEGF-A, -B, -C, -D, and placentagrowth factor PLGF.
VEGFR-2 is a high-affinity receptor for VEGF-A [1]. Theactivated VEGFR-2 binds Phospholipase C gamma 1 ( PLC-gamma 1 ) That leadsto the phosphorylation and activation of this protein and results in hydrolysis of themembrane Phosphatidylinositol (4,5)-bisphosphate ( PtdIns(4,5)P2 ) and generationof the second messengers 1,2-diacylglycerol ( DAG ) and inositol(1,4,5)-trisphosphate ( IP3 ). DAG is a physiological activator of Proteinkinase C beta 1 ( PKC-beta ), whereas IP3 binds to a specific receptorpresent on the endoplasmic reticulum, resulting in the release of intracellular storedCa(2+) [2].
PKC-beta phosphorylates and activates V-raf-1 murine leukemia viral oncogenehomolog 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/ Sphingosinekinase 1 ( SPK1 ) pathway [3]. SPK1 is an enzyme whichcatalyses Spingosine 1 phosphate formation from Sphingosine.Decrease of sphingosine concentration and increase of sphingosine1-phosphate leads to activation of V-Ha-ras Harvey rat sarcoma viral oncogenehomolog ( H-Ras ), apparently through inhibition of Neurofibromin and RASp21 protein activator 1 ( p120GAP ). H-Ras in turn binds to and activatesc-Raf-1 leading to Erk (MAPK1/3) activation. Activated Erk(MAPK1/3) activates by phosphorylation Jun oncogene( c-Jun ). The latter oneforms 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 signalthrough Conserved helix-loop-helix ubiquitous kinase ( IKK-alpha ) and Inhibitorof kappa light polypeptide gene enhancer in B-cells kinase beta ( IKK-beta ) toI-kB/ NF-kB pathway. [5], [6]. NF-kBactivates transcription of Intercellular adhesion molecule 1 ( ICAM1 ), Vascularcell 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 catalyticsubunits of PI3K - PI3K cat class IA, which, in turn, results in an increase inlipid Phosphatidylinositol (3,4,5) ( PtdIns(3,4,5)P3 ) and activation of V-aktmurine thymoma viral oncogene homolog 1 AKT(PKB). The AKT(PKB) signalingpathway regulates cellular survival by inhibiting pro-apoptotic pathways [2].
Brca1 represses the activity of VEGF-A via ESR1 and SP1and SP3 [8], [9].
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