Back to the roots: the remarkable RAF oncogene story.

RAF kinases entered the limelight when our understanding of the genetic nature of cancer was much less defined and the seminal importance of proto-oncogenes as components of intracellular signaling pathways was just beginning to be recognized. Following the discovery of the v-RAF oncogene and the subsequent description of the c-RAF-1 gene by the group of Ulf Rapp, the last 20 years have seen the dissection of the signaling pathways in which RAF kinases function, and the cellular processes they control. The recent demonstration of mutations in B-RAF and C-RAF in human tumors marked the return of RAF kinases to their roots as oncogenes. The availability of small molecular weight inhibitors has fueled the hope for new therapeutic approaches. Despite the deep insights gained through the work of many laboratories, the past has left us with sufficient controversy and plenty of open questions to keep RAF research as interesting as ever.