Elucidation of the RAF dimerization underlying mechanisms as the basis for the development of effective drugs in cancer treatment

• Applicant: Dr. Angela Baljuls
• Subject Area: Cell Biology
• Term: from 2011 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 215979924

RAF inhibitors are increasingly used in cancer therapy. However, paradoxical activation of the MAPK cascade induced by specific RAF inhibitors turned out to be an unexpected obstacle. The reason for this phenomenon is supposed to be the inhibitor-induced RAF dimerization. The underlying mechanisms of RAF dimerization are not sufficiently explored. One of the open questions is, whether this dimerization occurs directly through the contact between the surfaces of two RAF molecules, or indirectly through the binding to the 14-3-3 adapter proteins. In this regard, the published data that has been obtained in vitro with the separated catalytic domain is insufficient. Therefore, the elucidation of the RAF dimerization under native conditions is an important challenge. Furthermore, the question will be addressed, whether and to what extent the ERK-mediated feedback regulation affects the RAF dimerization. The planned work is based on the recent finding that the RKTR motif of RAF kinases is involved in both, the dimerization and feedback regulation. Also, there is evidence that the regulation of cellular processes is determined not only by activation/deactivation of RAF, but also by its subcellular localization and substrate specificity. This was recently demonstrated by the RAF-mediated regulation of the pro-apoptotic protein BAD. In cancer cells carrying an activating B-RAF mutation, BAD lost its pro-apoptotic function and promoted cell proliferation. The further clarification of these processes under the aspect of the RAF dimerization is an additional aim of this project. My ambition is to combine my own know-how with the experience of the host laboratory to provide a basis for improving the application of the RAF inhibitors in cancer therapy.

• DFG Programme: Research Fellowships
• International Connection: Ireland
• Host: Professor Dr. Walter Kolch