RAF Protein Family
Regulation and Biological Activity of the RAF Protein Family
Investigators: R Marais, T Ahmad, N Dumaz, V Emuss, M Garnett, V Gray-Schopfer, R Hayward, R Kirk, S Rana, S da Rocha Diaz, C Wellbrock, S Whittaker; in collaboration with D Barford, Section of Structural Biology and C Springer, Cancer Research UK Centre for Cancer Therapeutics
The RAS/RAF/MEK/ERK signal transduction pathway is a conserved pathway that regulates cell growth and signalling through this pathways is elevated in approximately 30% of human cancers. There are three RAF proteins, A-RAF, B-RAF and C-RAF. RAS is muated in approximately 15% of human cancers and B-RAF is mutated in approximately 7%. B-RAF is particularly important in a form of skin cancer called, melanoma and is mutated in approximately 70% of cases. Over 50 different types of B-RAF mutations have been found in human cancers and we have shown that the majority of these are activating. The activated proteins stimulate constitutive signalling through the pathway in human cancer and they stimulate growth (proliferation) of the cells and protect them from a form of death called apoptosis. When the activity of mutant B-RAF is blocked, cells stop growing and die, demonstrating that B-RAF is a valuable and important therapeutic target for cancer treatments. We have initiated a joint venture with the Wellcome Trust, Cancer Research UK and Astex Technology Inc. to develop novel anti-B-RAF drugs that can be used to treat the forms of cancer that harbour B-RAF mutations. We have also solved the structure of B-RAF and this reveals a model of how the mutations in B-RAF activate the kinase in cancer. Essentially the kinase is normally trapped in an inactive form through an intra-molecular interaction involving two regions of the protein. In cancer the interaction is disrupted and so the protein is released into the active form. These studies are also guiding our drug discovery programme.
External Funding: Cancer Research UK, MRC, BBSRC
In the Section of Cell and Molecular Biology (including the Cancer Research UK Centre for Cell and Molecular Biology)
