Model for Ras-independent regulation of Raf-1 and MEK by EPO. Kinase(s) such as Pak3 phosphorylates Raf-1 at serine 338 to activate it. The activated Raf-1 phosphorylates MEK, which, in turn, phosphorylates ERK and unknown kinase(s). The unknown kinases then hyperphosphorylate Raf-1 in the carboxy-terminal domain to inactivate Raf-1 MEK kinase activity or to promote Raf-1 disassociation from MEK and translocation to Ras. In the presence of inhibitors, MEK cannot phosphorylate unknown kinase, and unknown kinase cannot phosphorylate Raf-1 in the carboxy-terminal domain to inactivate its MEK kinase activity or to promote its dissociation from MEK. Active Raf-1 prolongs the phosphorylation of MEK.