CLONING AND CHARACTERIZATION OF 2 DISTINCT HUMAN EXTRACELLULAR SIGNAL-REGULATED KINASE ACTIVATOR KINASES, MEK1 AND MEK2

Mitogen-induced signal transduction is mediated by a cascade of protei n phosphorylation and dephosphorylation. One of the immediate response s of mitogen stimulation is the activation of a family of protein kina ses known as mitogen-activated protein kinase or extracellular signal- regulated kinase (ERK). MEK (MAP kinase or ERK kinase) is the immediat e upstream activator kinase of ERK. Two cDNAs, MEK1 and MEK2, were clo ned and sequenced. MEK1 and MEK2 encode 393 and 400 amino acid residue s, respectively. The human MEK1 shares 99% amino acid sequence identit y with the murine MEK1 and 80% with human MEK2. Both MEK1 and MEK2 wer e expressed in Escherichia coli and shown to be able to activate recom binant human ERK1 in vitro. The purified MEK2 protein stimulated threo nine and tyrosine phosphorylation on ERK1 and concomitantly activated ERK1 kinase activity more than 100-fold. The recombinant MEK2 showed l ower activity as an ERK activator as compared with MEK purified from t issue. However, the recombinant MEK2 can be activated by serum-stimula ted cell extract in vitro. MEKs, in a manner similar to ERKs, are like ly to consist of a family of related proteins playing critical roles i n signal transduction.