Blue Ridge Institute for Medical Research

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The current focus of the Institute centers on targeted cancer therapies. More than 8 small molecule inhibitors of protein kinases have been approved by the FDA for the treatment of various cancers. Imatinib (Glevec), gefitinib (Iressa), erlotinib (Tarceva) and sunitinib (Sutent) are representative examples. Protein kinases catalyze the following reaction: 

MgATP1- + protein-OH  Protein-OPO32- + MgADP + H+

Based upon the nature of the phosphorylated –OH group, these enzymes are classified as protein-serine/threonine kinases and protein-tyrosine kinases. Investigators have identified 478 typical and 40 atypical protein kinase genes in humans (total 518) that correspond to about 2% of all human genes. The family includes 385 protein-serine/threonine kinases, 90 protein-tyrosine kinases, and 43 protein-tyrosine-kinase like proteins. Of the 90 protein-tyrosine kinases, a total of 58 are receptor and 32 are non-receptor in nature. The exons of the protein kinase family account for about 1.3 Mb or 2% the entire coding sequence of human DNA. The protein kinase family is the second largest enzyme family (after proteases) and the fifth largest gene family in humans.

Previous work considered the role of the Bcr-Abl protein kinase and its role in producing chronic myelogenous leukemia. Other studies have centered on the epidermal growth factor receptor family including HER1, HER2, HER3, and HER4 (Human Epidermal growth factor Receptors). Additional work has focused in the Src family of protein kinases and the stem cell factor protein kinase called Kit. 

More recent work has addressed the role of vascular endothelial growth factor and its receptors in the treatment of cancers."When tumors reach a size of about 0.2–2.0 mm in diameter, they become hypoxic and limited in size in the absence of angiogenesis. In order to increase in size, tumors undergo an angiogenic switch where the action of pro-angiogenic factors predominates, resulting in angiogenesis and tumor progression. One mechanism for driving angiogenesis results from the increased production of vascular endothelial growth factor (VEGF). This factor activates two VEGF protein-tyrosine kinase receptors (VEGFR1 and VEGFR2). Owing to the importance of angiogenesis in tumor progression, inhibition of VEGF signaling represents an attractive cancer treatment. 

The Raf-Mek-Erk protein kinase cascade plays an important role in cell proliferation, survival, and differentiation. It is downstream from Ras, a G-protein that is mutated in about 30% of all human cancers. There are three members of the Raf kinase family (A, B, and C). Bcr-Abl, HER1-HER4, Src, Kit, and VEGFR1-3 are protein-tyrosine kinases. In contrast, the Raf kinases are protein serine/threonine kinases. B-Raf kinase is mutated in about 7% of all human cancers. We are examining the regulation of the Raf kinases and the role they play in the production of cancer cells. 

Tyrosine hydroxylase is the first enzyme on the pathway for the biosynthesis of dopamine, norepinephrine, and epinephrine, which are important neurotransmitters. We are examining the structure, mechanism of action, and regulation of tyrosine hydroxylase under physiological conditions and in disease states such as Parkinson's disease and DOPA-responsive dystonias.

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Concentrate only on the biggest and most important biomedical research problems. – James D. Watsonn the 
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Updated 24 February 2011