Researchers report the cloning of a key group of human genes, the protein kinases
May 2, 2008Although the human genome has been sequenced, research into mechanism of action of genes has been hampered by the fact that most human genes have not been isolated. This is true for even the most common class of cancer-associated genes, the protein kinases, which mediate the majority of signaling events in cells by phosphorylating and modulating the activity of other proteins. It has been estimated by systematic gene sequencing efforts that up to a quarter of kinases may play a role in human cancers.
In a study published in the 2nd of May issue of Cell, a research teams led by Professor Jussi Taipale from the National Public Health Institute and University of Helsinki, Finland, Professor Olli Kallioniemi from Institute for Molecular Medicine Finland (FIMM), and Dr. Wei-Wu He from the US-based biotechnology company Origene Technologies, Inc., report cloning of nearly all predicted human protein kinase genes in functional form, and generation of a corresponding set of kinases lacking catalytic activity that are necessary for functional studies.
They further used the kinome collection in several high-throughput screens, including a screen which identified two novel kinases regulating the Hedgehog signaling pathway – a key pathway linked to multiple types of human cancer. In addition, together with the group of Dr. Päivi Ojala, University of Helsinki, they identified a novel kinase required for activation of Kaposi’s sarcoma herpesvirus.
“The isolated kinase genes form a resource that scientist can now use to systematically map kinase signaling networks in different cellular disease models. The kinases are also promising targets for therapeutic intervention in the treatment of various cancers”, Professor Taipale states.
Source: University of Helsinki
Nov 10, 2009 |
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Signal transduction is defined as any biochemical communication from one part of the cell to another. It is essential for normal functioning of the cell and is highly regulated. The process begins with a specific protein called a receptor that is bound in the cell surface membrane. The portion of the receptor that faces the exterior of the cell contains a ligand or site that can bind to a signaling molecule. This binding results in the activation of the receptor. The interior portion of the receptor is either a functional enzyme, or can combine with and activate an enzyme.
Receptors for most growth factors are enzymes called tyrosine kinases. Signal transduction can be described as a cascade or reactions, in which a chemical change in one molecule leads to change in another molecule (mostly proteins). The signaling process begins when the enzyme receives a phosphate group from ATP, an energy generating molecule present in the cell. The phosphate group is then transferred to a series of protein kinase molecules in turn. The process continues until an activated molecule enters the nucleus, where it results in the activation of genes responsible for functioning of the cell cycle and cell division.
The cancer state is typically characterized by a signaling process that is unregulated and in a continuous state of activation. This may be due to the action of oncogenes, or genes that code for abnormal proteins that are themselves kinase enzymes or otherwise activate the signaling process. Gene mutations of cancer could also alter the receptor molecule in a manner that it remains active without regulation. The signal transduction pathways are very complex and still not completely understood. All proteins in the pathways are potential candidates for inhibition.
Epidermal growth factor receptors (EGFR) are typical enzyme-linked receptors, with an exterior ligand that binds with a signaling molecule, and an internal tyrosine kinase enzyme site. Drugs are developed to inhibit expression at either of these sites. Iressa binds to the external ligand, and has shown activity against non-small-cell lung cancer, adenocarcinoma and breast cancer. In the case of breast cancer, Iressa inhibits an overactive HER/neu tyrosine kinase. The monoclonal antibody, Erbitux, also binds to and inhibits the external ligand of EGFR. This antibody shows promise for use in patients with head a neck cancer who have developed resistance to chemotherapy.
Since unregulated signal transduction is a primary characteristic of many types of cancers, researchers are very active in the pursuit of inhibitors that can control the process. These drugs promise to become an essential part of the physician's armament against cancer, particularly those cancers that have developed resistance to other forms of treatment.
However, setbacks with Gleevec and Iressa, that specifically target protein kinases, reflect a lack of validated biomarkers. The next classes of signal transduction inhibitors, the vascular endothelial growth factor receptor (VEGFR) also lack validated biomarkers.
What is needed is to test the concept of targeted cancer drugs with biomarkers as pharmacodynamic endpoints, and with the ability to measure multiple parameters in cellular screens now in hand using flow cytometry.
The importance of mechanistic work around targets as a starting point for drug development should be downplayed in favor of a systems biology (cell function analysis) approach were compounds are first screened in cell-based assays, with mechanistic understanding of the target coming only after validation of its impact on the biology.
Gleevec turned out to be one of the first examples of a multi-targeted kinase inhibitor. The lessons learned from the Gleevec experience are that mutant kinase targets are a smoking gun for kinase dependency, resistance reveals tumor heterogeneity, and the conformation of the kinase (active or inactive) may be important when choosing drug leads to take into the clinic. In such molecules, different portions bind to different sites on kinases. Given the heterogeneity of tumors among people with cancer (and even in the same person over time), multiple drugs give clinicians an opportunity to vary dosing in proportion to the specific person's tumor expression profile and the pathways activated in that individual.
The fundamental role of kinases in cancer biology and the success of pioneering therapeutics have prompted intensive efforts to develop kinase inhibitors. However, many of these drugs cry out for validated clinical biomarkers to help set dosage and select people likely to respond.