VEGF Signaling
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. Upon binding, they get activated through transphosphorylation and dimerize. 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 of 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.
VEGF signaling is essential for normal vascular development and homeostasis. However, under pathological conditions, high levels of VEGF may induce the formation of pathological vessels through angiogenesis. Thus, VEGF signaling is induced after an ischemic stroke or upon CNS injury and may cause cerebral angiogenesis, increased blood-brain barrier permeability, and dysfunction. VEGF not only facilitates tumor angiogenesis but also acts as a survival factor for metastatic cells. In breast cancer, for example, VEGF directly influences tumor invasion and migration, with reduced VEGF expression leading to increased apoptosis in metastatic cells. VEGF overexpression may also lead to 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.
VEGF signaling also plays a role in non -endothelial cells, such as epithelial cells. For instance, VEGF/VEGFR-2 signaling has been shown to stimulate bile duct proliferation in both autocrine and paracrine manners, suggesting its involvement in biliary epithelial cell biology under normal and pathological conditions.
Related Pathways and Resources
References:
- : "VEGF receptor signal transduction." in: Science's STKE : signal transduction knowledge environment, Vol. 2001, Issue 112, pp. re21, (2002) (PubMed).
- : "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).
- : "Varicella-zoster virus infection of human astrocytes, Schwann cells, and neurons." in: Virology, Vol. 179, Issue 2, pp. 834-44, (1990) (PubMed).
- : "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).
- : "New insights on the role of vascular endothelial growth factor in biliary pathophysiology." in: JHEP reports : innovation in hepatology, Vol. 3, Issue 3, pp. 100251, (2021) (PubMed).
