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Kinase Inhibitors

Kinase Function in the Cell
The kinases include a large number of enzymes that regulate the activity of other proteins and, more indirectly, the activities of cells. All kinases add phosphate groups to other molecules, often other proteins, in the cell. Protein phosphorylation, the addition of a phosphate group to a side chain of an amino acid(1), is an important regulatory action. Because each phosphate group carries two negative charges, the addition of one of a phosphate can cause a change in the shape of a protein. Altered protein shape is often correlated with altered activity of the protein. The ability to change the conformation of a protein between two different shapes allows for regulated control of that protein's activity. Phosphorylation (addition of phosphate groups to a protein) by kinases is a reversible process,and proteins can be dephosphorylated (removal of phosphate group) by enzymes called protein phosphatases.(1)These two groups of enzymes often work together to 'turn on' and 'turn off' pathways within cells. The kinases play an important role in many intracellular signaling pathways, including those that control cell growth and cell division.

The animation below depicts phosphorylation. The kinase represented in green has two binding sites, one for ATP (shown in red) and the other for binding the target molecule (shown in purple). After binding at both sites occurs the phosphate (shown in yellow) is transferred from ATP to the target molecule altering its structure and activity. Learn more about kinases by watching the full interview with Dr. William Hahn.



Kinases and Cancer
Cell growth and cell cycle pathways are constitutively activated in cancer cells. The normal controls exerted by the kinase/phosphatase enzymes no longer function.One key feature of cancer cells is their ability to reproduce in the absence of external signals such as growth factors. In the normal process, growth factors that are excreted by other cells bind to receptors on the cell surface, stimulating the cell to divide. Cancerous cells turn on the pathway in the absence of the growth factor. This may occur because of a mutation in a kinase or phosphatase gene. In one example, chronic myeloid leukemia, a particular chromosomal translocation (termed the Philadelphia chromosome) has been identified that creates a novel kinase that is 'on' all the time. The pathway that this kinase controls is, in effect, stuck in the 'on' position. This leads to proliferation of the cancerous cells.

Several new cancer treatments are designed to inhibit aberrantly activated kinases within cancer cells in an effort to prevent cell division. The following drugs are kinase inhibitors used to treat cancer.

References for this page:
  1. Becker, Hardin, Kleinsmith. The World of the Cell. San Francisco: Benjamin Cummings, 2003.
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