The protein products of the raf gene family are serine/threonine protein kinases. Raf kinases are involved in relaying mitogenic signals from the cell surface to the nucleus. They consist of two functional domains, the amino-terminal regulatory half and the carboxy-terminal catalytic half. Upon stimulation, the phosphorylation level of Raf proteins increases with modification mostly occurring on serines, threonines, and in the case of some mitogens on tyrosines. The four major sites of serine phosphorylation on Raf-1 were mapped in collaboration with Dr. D. Morrison to positions 42, 259, 285 and 620. In addition, Thr268 is modified and tyrosine phosphorylation occurs either at position 340 or 232. Mutations altering site 42 confer a slightly activated phenotype, while mutations involving position 259 are overly activated, and those at position 620 cause a dominant negative phenotype. In addition to phosphorylation, which mostly occurs in the regulatory domain, the protein is also regulated by other factors, most likely the interaction with low molecular weight ligands. Mutations interfering with a cysteine array, also located in the regulatory half, result in activated Raf-1, suggesting that this structure might be responsible for this type of interaction.
