RAF Kinases: Pathway, Modulation and Modeling

The Ras/RAF/MEK/ERK cascade is a central cellular signal transduction pathway involved in cell proliferation, differentiation, and survival where RAF kinases are pivotal kinases implicated in cancer.
The development of specific irreversible kinase inhibitors is a rewarding but difficult aim. A novel synthetic approach including a lyophilization step allowed us the synthesis of a diphenyl urea compound with an epoxide moiety (compound 1). Compound 1 possessed inhibitory activity in vitro. In cell culture experiments, a strong activation of the RAF signaling pathway was observed, an effect which is known from several other RAF kinase inhibitors and is here reported for the first time for a diphenyl urea compound.
Furthermore, we developed a mathematical model of the Ras/RAF/MEK/ERK cascade demonstrating how stimuli induce different signal patterns and thereby different cellular responses, depending on the ratio between B-RAF and C-RAF.
Additionally the effect of the tumor suppressor DiRas3 (also known as Noey2 or ARHI) on RAF signaling was studied. I could show that DiRas3 down-regulates the mitogenic pathway by inhibition of MEK.

Autorentext
I was born in Tehran-Iran but I moved to Austria at the age of six. After studying Chemical Engineering at the Technical University of Vienna, I moved to Göteborg--Sweden were I did my Master of Science in Bioinformatics. Thereafter I moved to Germany and did my doctorate in Bioinformatics at the University of Würzburg.