Raf1 is a MAP kinase kinase kinase (MAP3K), which functions downstream of the Ras family of membrane associated GTPases to which it binds directly. Activation of Raf1 is the best understood and involves phosphorylation at multiple activating sites including Ser338, Tyr341, Thr491, Ser494, Ser497, and Ser499. The hyperphosphorylation of these six sites is dependent on downstream MEK signaling and renders Raf1 unresponsive to subsequent activation events. Raf1 is broadly expressed in nearly all cell lines tested to date and is the cellular homolog of v-Raf. The unregulated kinase activity of the v-Raf protein has been associated with transformation and mitogenesis while the activity of Raf-1 is normally suppressed by a regulatory N-terminal domain.
