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(Boston) — Researchers at Boston University Medical Campus have for the first time identified an enzyme known as Casitas B-lineage lymphoma (c-Cbl) that is activated by VEGF receptor 2. Activated c-Cbl binds to and suppresses enzymatic activity of enzyme known as Phospholipase C-gamma1 (PLC1) and of growth of new blood cells (angiogenesis). The study appears in the online early edition of the Proceedings of the National Academy of Sciences.
Angiogenesis plays a central role in many diseases, from the growth of malignant tumors to the loss of vision associated with diabetic eye disease or macular degeneration. The molecule known to play central role in the development of these abnormal vessels is vascular endothelial growth factor (VEGF).
In order for VEGF to initiate the growth of blood vessels, it must first bind to a specific site on the cells that form the blood vessel wall. These sites are called VEGF receptors. Once VEGF is produced by diseased tissue, it binds to a cell surface receptor known as VEGF-receptor-2 (VEGFR-2). Until now, much of what happens after this point, which leads to proliferation of new blood vessels has been unknown.
Several years ago, these same researchers showed that activation of the enzyme PLC-gamma1 is essential for VEGF to promote angiogenesis. Now, they have shown that c-Cbl antagonizes angiogenesis by promoting ubiquitination of PLC-gamma 1 and suppression of its tyrosine phosphorylation. “Ubiquitination is known to be the kiss of death for a protein. Once a target protein is tagged with ubiquitin, it is destined for degradation,” said senior author Nader Rahimi, PhD, an associate professor at Boston University.
According to Rahimi this work is important because it reveals, for the first time, that c-Cbl suppresses angiogenesis by promoting ubiquitination of PLC-gamma1. “This finding provides a basis for developing a new approach to anti-angiogenesis therapy whether for cancer, or other conditions such as AMD and diabetic retinopathy. The mechanism described in this paper for inhibition of angiogenesis at the level of PLC-gamma 1 and c-Cbl raises the possibility that drugs designed to target these proteins could also be used to treat angiogenesis-associated diseases,” he adds.