Activation of the MAP kinase pathway by the protein kinase raf

Both MAP kinases and the protein kinase p74 raf-1 are activated by many growth factors in a c-ras-dependent manner and by oncogenic p21 ras . We were therefore interested in determining the relationship between MAP kinases and raf. The MAP kinase ERK2 is activated by expression of oncogenically activated raf, independently of cellular ras. Overexpressed p74 raf-1 potentiates activation of ERK2 by EGF and TPA. MAP kinase kinase inactivated by phosphatase 2A treatment is phosphorylated and reactivated by incubation with p74 raf-1 immunoprecipitated from phorbol estertreated cells. We conclude that raf protein kinase is upstream of MAP kinases and is either a MAP kinase kinase kinase or a MAP kinase kinase kinase kinase.