Cell Signalling Group
Group Leader: Dr Pablo Rodriguez-Viciana
We use biochemistry, molecular and cellular biology as well as transgenic models to study how RAS family GTPase signal and carry out their multiple cellular functions. Using genomic and proteomic approaches we have identified several novel signalling pathways regulated by different members of the RAS family. Our overall goal is to characterize these novel RAS family effector pathways and to analyze their roles in tumourigenesis, with the ultimate aim of identifying and validating novel targets of therapeutic intervention for the treatment of human cancer.
RAS genes (H-, N- and K-RAS) are mutated in ~30% of human tumours and likely play a role by indirect activation (e.g. by receptor tyrosine kinases) in an even larger number of cancers. RAS mutations are also found in developmental disorders such as Costello and Noonan syndrome.
RAS proteins function as molecular switches, with ON and OFF states. They are activated in response to extracellular signals and when in their ON state, interact with a wide array of downstream targets or effectors to regulate multiple biological processes, including proliferation, differentiation, survival and motility. Analysis of mutations in human tumours has validated both RAF and PI3-kinase as crucial RAS effectors in human tumourigenesis and both are the subject of intense research by pharmaceutical companies. However, data from a variety of experimental systems strongly suggests that additional effectors play critical contributions to RAS-induced tumour formation.
RAS proteins belong to a family of closely related GTPases called the RAS family. Several members of this family share biochemical and biological properties with the RAS proteins, including the ability to act as oncogenes. Their roles in tumourigenesis and how signalling specificity is achieved among closely related members is still poorly understood.
• Kristina Klupsch PhD (Research Fellow)
• Marta Munoz-Alegre MPhil (Research Assistant)
• Nicole Hartig MSc (PhD student)
• Berna Demiray MSc (PhD student)
• Anne Roehrig MSc (PhD student)
• Lucy Young BSc (Research Technician)
Rodriguez-Viciana, P., Tetsu, O., Tidyman, W. E., Estep, A. L., Conger, B. A., Cruz, M. S., McCormick, F., and Rauen, K. A. (2006). Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome. Science 311, 1287-1290. Pubmed
Rodriguez-Viciana, P., Oses-Prieto, J., Burlingame, A., Fried, M., and McCormick, F. (2006). A phosphatase holoenzyme comprised of Shoc2/Sur8 and the catalytic subunit of PP1 functions as an M-Ras effector to modulate Raf activity. Mol Cell 22, 217-230. Pubmed
Rodriguez-Viciana, P., Collins, C. and Fried, M. (2006). Polyoma and SV40 proteins differentially regulate PP2A to activate distinct cellular signaling pathways involved in growth control. Proc Natl Acad Sci, 103, 19290-19295. Pubmed
Rodriguez-Viciana, P., and McCormick, F. (2005). Characterization of interactions between Ras family GTPases and their effectors. Methods Enzymol 407, 187-194. Pubmed
Rodriguez-Viciana, P., Collins, C. H., Moule, M. G., and Fried, M. (2006). Chromosomal instability at a mutational hotspot in polyoma middle T-antigen affects its ability to activate the ARF-p53 tumor suppressor pathway. Oncogene 25, 1454-1462. Pubmed
Rodriguez-Viciana, P., Tetsu, O., Oda, K., Okada, J., Rauen, K. and McCormick, F. (2005) Cancer targets in the Ras pathway. Cold Spring Harb Symp Quant Biol, 70, 461-467. Pubmed