Mitogen-activated protein (MAP) kinase cascades are activated by various extracellular stimuli including growth factors. The MEK kinases (also called MAP kinase kinase kinases) phosphorylate and activate the MAP kinases, including ERK, JNK and p38. The MEK kinases characterized to date include Raf-1, Raf-B, MOS, MEK kinase-1, MEK kinase-2, MEK kinase-3, MEK kinase-4 and ASK 1 (also designated MEK kinase-5). MEK kinase-1 has been shown to phosphorylate MEK-1 via a Raf-independent pathway. Evidence suggests that MEK-3 is preferentially activated by MEK kinase-3 and that MEK-4 is activated by both MEK kinase-2 and MEK kinase-3. MEK kinase-4 has been shown to specifically activate the JNK pathway. ASK1 activates both MEK-4 and MEK-3/MEK-6 pathways.