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From Proteopedia

Current revision

Vascular Endothelial Growth Factor (VGEF)

Function

Vascular Endothelial Growth Factor is a signaling protein that acts as a ligand to tyrosine kinases embedded in the cellular membrane involved in the regulation of angiogenesis. By doing this, VEGF is able to regulate physiological and pathological angiogenesis, or blood and lymph vessel development. Along with promoting mitosis and angiogenesis, VEGF also enhances permeability such as that of the blood vessels. Because this growth factor has dual functionality, there are many different isotopes of this protein, each allowing more of one function than the other. For example, 121 VEGF is more diffusible than 165 because it does not perform heparin binding, or binding to erythrocytes.

The structure of VEGF and the proteins to which it binds has been discovered through electron microscopy and x-ray crystallography; one of ligand VEGF-A and enzyme VEGFR-1ECD shows that there is a kinked region in the ligand. This kinked region corresponds to an area similarly kinked in the enzyme, allowing for binding. Additionally, microscopy and modeling has revealed that VEGF has three loops, which vary for each isotope, and these interact with the receptor ECD, allowing it to bind to the active site. However, this growth factor does not have the same rate of binding to active sites in all cells. Endothelial cells have proteins that have a binding site with high affinity for VEGF; this is what allows VEGF to primarily act on the endothelial cells and promote growth in the blood and lymph vessels [1].

Relevance

Lung cancer is a leading cause of death; taking the lives of nearly 30% of all cancer related deaths in the United States. The median survival time of a patient is only eight to ten months. Engineers have postulated that targeting the formation of blood vessels supplying the tumor is a potential way to control the growth of the tumor. This lead to the development of a new antibody called bevacizumab. This antibody is anti-vascular endothelial growth factor, meaning it works to diminish the effects that VEGF has on the growth of cancer. An experiment was designed that divided patients into three subgroups: a control group, an experiment group given 7.5 mg/kg dose of bevacizumab, and an experimental group given 15 mg/kg dose of bevacizumab. The results of the experiment showed an overall improvement in survival rate by two months in patients who received the antibody paired with regular chemotherapy[2].

Structural highlights

This scene shows the main chains that make up the VEGF protein. This scene shows the amino acid residues necessary for VEGF to bind to a VEGFR 1 Kinase. This scene shows the amino acid residues necessary for VEGF to bind to a VEGFR 2 Kinase.

References

[1] Markovic-Mueller S, Stuttfeld E, Asthana M, Weinert T, Bliven S, Goldie K, Kisko K, Capitani G, Ballmer-Hofer K. Structure of the Full-length VEGFR-1 Extracellular Domain in Complex with VEGF-A. 2017; 25(2): 341-352. http://www.sciencedirect.com/science/article/pii/S0969212616304026. Accessed February 20, 2018.

[2] Klamerus JF, Brahmer JR. Optimizing the Dose and Schedule of Anti–Vascular Endothelial Growth Factor Antibodies in Non–Small-Cell Lung Cancer. Clinical Lung Cancer. ELSEVIER. 2008;9(2): https://www.sciencedirect.com/science/article/pii/S1525730411702522?via%3Dihub. Accessed February 20, 2018.