PROPERTIES OF MEKS, THE KINASES THAT PHOSPHORYLATE AND ACTIVATE THE EXTRACELLULAR SIGNAL-REGULATED KINASES

Activation of extracellular signal-regulated kinase (ERK) or mitogen-a ctivated protein kinase by MEK (mitogen-activated protein kinase or ex tracellular signal-regulated kinase kinase) is an essential event in t he mitogenic growth factor signal transduction. We now demonstrate tha t three recombinant MEKs (MEK1, MEK2, MEK3) show remarkably different activity toward recombinant ERK1 and ERK2. MEK2 is the most active ERK activator. The recombinant MEK1 has an activity approximately seven t imes lower than that of MEK2. MEK3, which is identical to MEK1 except for missing an internal 26-amino acid residue and probably represents an alternative splicing product of MEK1, shows neither autophosphoryla tion nor ERK-activating activity. Recombinant MEK1 and MEK2 can be act ivated by epidermal growth factor-stimulated SWISS3T3 cell lysate. MEK 1 and MEK2 can also be activated by autophosphorylation. Autophosphory lation of MEKs correlates with their ability to phosphorylate and acti vate ERKs. Phosphorylation of MEK is also stimulated by ERK. Phosphoam ino acid analysis showed that ERK1 preferentially phosphorylated threo nine residue of MEKs. MEKs complex with ERKs in vitro. Interestingly, MEK3 also forms a complex with ERK1, although it is totally inactive a s an ERK activator.