Second nature: biological functions of the Raf-1 "kinase".

More than 20 years ago, Raf was discovered as a cellular oncogene transduced by transforming retroviruses. Since then, the three Raf isoforms have been intensively studied, mainly as the kinases linking Ras to the MEK/ERK signaling module. As this pathway is activated in human cancer, the Raf kinases are considered promising therapeutic targets, and we have learned a lot about their regulation, targets, and functions. Do they still hold surprises? Recent gene targeting studies indicate that they do. This review focuses on the regulation and biology of the best-studied Raf isoform, Raf-1, in the context of its kinase-independent functions.