Mitogen-activated protein (MAP) kinase cascades are activated by various extracellular stimuli including growth factors. The MEK kinases (also designated MAP kinase kinase kinases, MKKKs, MAP3Ks or MEKKs) phosphorylate and thereby activate the MEKs (also called MAP kinase kinases or MKKs), including ERK, JNK and p38. These activated MEKs in turn phosphorylate and activate the MAP kinases. The MEK kinases include Raf-1, Raf-B, Mos, MEK kinase-1, MEK kinase-2, MEK kinase-3, MEK kinase-4, ASK 1 (MEK kinase-5) and MAP3K6 (MEK kinase-6). 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.