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VEGF Signaling

Written/Edited by Julian Pampel, BSc

Vascular endothelial growth factors (VEGFs) constitute a sub-family of growth factors that stimulate the growth of new blood vessels. VEGFs are important signaling proteins and initiate angiogenesis via several signalling cascades. All members of the VEGF family stimulate cellular responses by binding to tyrosine kinase receptors (VEGFRs) on the cell surface. VEGFR-2 appears to mediate almost all of the known cellular responses to VEGF1. After receptor dimerization and autophosphorylation, several SH2 domain-containing signal transduction molecules are activated such as PLC-γ), VRAP (VEGF Receptor-Associated Protein), Sck, and Src2.

PLC-Gamma catalyzes the hydrolysis of PIP2 (Phosphatidylinositol-4, 5-Bisphosphate), creating IP3 (Inositol Trisphosphate) and DAG (Diacylglycerol), which stimulate the release of Ca2+ from internal stores. Ca2+ release promotes NO (Nitric Oxide) production via NOS (Nitric Oxide Synthase) as well as activativation PKC (Protein Kinase-C). NO regulates hematopoiesis and modulates cell growth.Together with PKC activation via DAG, the formation of SHC-GRB2-SOS complex enables the Raf1-MEK-ERK pathway3. Cell survival signal is mainly mediated through PI3K-mediated activation of Akt/PKB (Protein Kinase-B). BAD as well as Caspase-9 can inactivate Akt/Pkb ultimately leading to apoptosis instead of cell survival. p38 pathway transduces the VEGF information concerning Actin organization via MAPKAPK2/3 (MAP Kinase Activated Protein Kinase-2/3) and phosphorylation of the F-Actin polymerization modulator, HSP27 (Heat Shock Protein-27). The activation of PTK2 and Paxillin over VEGFR2 leads to recruitment Talin and Vinculin to the focal adhesion plaque4. These Actin-anchoring proteins further support actin reorganization5.

When VEGF is overexpressed, it can contribute to disease. Cancers that can express VEGF and establish blood supply are able to grow and metastasize. Another possible result are vascular disease in the retina of the eye and other parts of the body. Drugs such as Pegaptnib, Bevacizumab, and Ranibizumab can inhibit VEGF and control or slow those diseases.


  1. Matsumoto, Claesson-Welsh: "VEGF receptor signal transduction." in: Science's STKE : signal transduction knowledge environment, Vol. 2001, Issue 112, pp. re21, (2002) (PubMed).
  2. Harmer, DeFranco: "Shc contains two Grb2 binding sites needed for efficient formation of complexes with SOS in B lymphocytes." in: Molecular and cellular biology, Vol. 17, Issue 7, pp. 4087-95, (1997) (PubMed).
  3. Assouline, Levin, Major, Forghani, Straus, Ostrove: "Varicella-zoster virus infection of human astrocytes, Schwann cells, and neurons." in: Virology, Vol. 179, Issue 2, pp. 834-44, (1990) (PubMed).
  4. Ganju, Munshi, Nair, Liu, Gill, Groopman: "Human immunodeficiency virus tat modulates the Flk-1/KDR receptor, mitogen-activated protein kinases, and components of focal adhesion in Kaposi's sarcoma cells." in: Journal of virology, Vol. 72, Issue 7, pp. 6131-7, (1998) (PubMed).

(5) David O. Bates: "Vascular endothelial growth factors and vascular permeability" in: Cardiovasc Res. ; 87(2): 262–271, (2010)

Adaptor Proteins & Growth Factors

VEGFA (Vascular Endothelial Growth Factor A):

FLT4 (Fms-Related Tyrosine Kinase 4):

SH2D2A (SH2 Domain Protein 2A):

SHC2 (SHC (Src Homology 2 Domain Containing) Transforming Protein 2):

TGFB1I1 (Transforming Growth Factor beta 1 Induced Transcript 1):

GTPases & Ca2+ Cycle

CHP (Calcium Binding Protein P22):

CDC42 (Cell Division Cycle 42 (GTP Binding Protein, 25kDa)):

HRAS (HRas proto-oncogene, GTPase):

NANOS3 (Nanos Homolog 3):

NFAT1 (Nuclear Factor of Activated T-Cells, Cytoplasmic, Calcineurin-Dependent 2):

RAC2 (Ras-Related C3 Botulinum Toxin Substrate 2 (Rho Family, Small GTP Binding Protein Rac2)):

RAC3 (Ras-Related C3 Botulinum Toxin Substrate 3 (Rho Family, Small GTP Binding Protein Rac3)):


JMJD7-PLA2G4B (JMJD7-PLA2G4B Readthrough):

PLA2G4A (Phospholipase A2, Group IVA (Cytosolic, Calcium-Dependent)):

PLA2G4B (Phospholipase A2, Group IVB (Cytosolic)):

PLA2G4C (Phospholipase A2, Group IVC (Cytosolic, Calcium-Independent)):

PLA2G4D (phospholipase A2, Group IVD (Cytosolic)):

PLA2G4E (Phospholipase A2, Group IVE):

Protein Kinases & HSPs

Protein Phosphatases

PIK3CA (Phosphoinositide-3-Kinase, Catalytic, alpha Polypeptide):

PIK3R5 (Phosphoinositide-3-Kinase, Regulatory Subunit 5):

PPP3CA (Protein Phosphatase 3, Catalytic Subunit, alpha Isoform):

PPP3CB (Protein Phosphatase 3, Catalytic Subunit, beta Isozyme):

PPP3CC (Protein Phosphatase 3, Catalytic Subunit, gamma Isozyme):

PPP3R1 (Protein Phosphatase 3, Regulatory Subunit B, alpha):

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