Pathway Map Details

Development_VEGF signaling via VEGFR2 - generic cascades



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Ca('2+) cytosol, PI3K reg class IA, SPHK1, MEK2 (MAP2K2), PtdIns(3,4,5)P3, PKC-alpha, PI3K cat class IA, PKC, PtdIns(4,5)P2, Ca('2+) = Ca('2+), 2.7.1.-, NO, c-Src, VEGFR-2, PLC-gamma 1, AKT(PKB), Neurofibromin, MEK1 (MAP2K1), c-Raf-1, IKK-beta, (L)-Arginine (cytosol), eNOS, DAG, sphingosine, Sphingosine 1-phosphate, H-Ras, IKK-alpha, 3.1.4.11, IKK-gamma, (L)-Citrulline cytosol, Ca('2+) endoplasmic reticulum lumen, I-kB, NF-kB p50/p65, IP3, ERK1/2, 2.7.1.137, CCL2, c-Jun, p120GAP, PKC-beta, IP3 receptor, VEGF-A, c-Jun/c-Fos, 1.14.13.39, IKK (cat)

Description:

VEGF signaling via VEGFR2 - generic cascades

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, which currently consists of five members ( VEGF-A, VEGF-B, VEGF-C, VEGF-D, and Placenta growth factor ( PLGF )).

VEGFR-2 is a high-affinity receptor for VEGF-A [1]. Activated VEGFR-2 binds Phospholipase C gamma 1 ( PLC-gamma 1 ) leading to its phosphorylation and activation, which 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+) [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) ) and Mitogen-activated protein kinase kinase 2( MEK2 (MAP2K2) )/ Mitogen-activated protein kinase 3/1 ( ERK1/2 ) signaling cascade. ERK1/2 can also be activated through PKC/ Sphingosine kinase 1 ( SPHK1 ) pathway [3]. 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 [4], [5].

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 Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor ( I-kB)/Nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 and V-rel reticuloendotheliosis viral oncogene homolog A ( NF-kB p50/p65 ) pathway. NF-kB p50/p65 together with c-Jun/c-Fos activate transcription of Chemokine ligand 2 ( CCL2 ) [6], [7]

VEGFR-2 also binds and activates Phosphoinositide-3-kinase regulatory subunit (PI3K reg class IA ) [8], followed by activation of catalytic subunits of PI3K - PI3K cat class IA, which, then results in an increase in lipid Phosphatidylinositol 3,4,5-triphosphate ( PtdIns(3,4,5)P3 ) and activation of V-akt murine thymoma viral oncogene homolog 1 ( AKT(PKB) ).

AKT(PKB) signaling pathway regulates cellular survival by inhibiting pro-apoptotic pathways [2]. AKT(PKB) can directly phosphorylate Nitric oxide synthase 3 ( eNOS ) leading to nitric oxide production [9], [10]. Another mechanism of eNOS activation involves V-src sarcoma viral oncogene homolog ( c-Src ) and PLC-gamma 1: VEGF-A receptor binding causes c-Src activation with subsequent phosphorylation of PLC-gamma 1 leading to increases in intracellular levels of IP3 and elevation of intracellular calcium. Increase in intracellular calcium concentration stimulates Nitric oxide synthase 3 ( eNOS ) to produce nitric oxide [11].

References:

  1. 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
  2. Cross MJ, Dixelius J, Matsumoto T, Claesson-Welsh L
    VEGF-receptor signal transduction. Trends in biochemical sciences 2003 Sep;28(9):488-94
  3. 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
  4. Takahashi T, Ueno H, Shibuya M
    VEGF activates protein kinase C-dependent, but Ras-independent Raf-MEK-MAP kinase pathway for DNA synthesis in primary endothelial cells. Oncogene 1999 Apr 1;18(13):2221-30
  5. 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
  6. 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
  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
  8. 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
  9. Fulton D, Gratton JP, McCabe TJ, Fontana J, Fujio Y, Walsh K, Franke TF, Papapetropoulos A, Sessa WC
    Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature 1999 Jun 10;399(6736):597-601
  10. Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher AM
    Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature 1999 Jun 10;399(6736):601-5
  11. He H, Venema VJ, Gu X, Venema RC, Marrero MB, Caldwell RB
    Vascular endothelial growth factor signals endothelial cell production of nitric oxide and prostacyclin through flk-1/KDR activation of c-Src. The Journal of biological chemistry 1999 Aug 27;274(35):25130-5