A family of protein kinases located upstream of the MAP kinases and responsible for their activation has been identified. The prototype member of this family, designated MAP kinase kinase, or MEK-1, specifically phosphorylates the MAP kinase regulatory threonine and tyrosine residues present in the Thr-Glu-Tyr motif of ERK. A second MEK family member, MEK-2, resembles MEK-1 in its substrate specificity. MEK-3 (or MKK-3) functions to activate p38 MAP kinase, and MEK-4 (also called SEK1 or MKK-4) activates both p38 and JNK MAP kinases. MEK-5 appears to specifically phosphorylate ERK-5, whereas MEK-6 phosphorylates p38 and p38β. MEK-7 (or MKK-7) phosphorylates and activates the JNK signal transduction pathway.