PD98059

Background

The MAPK (Erk) kinases MEK1 and MEK2 are dual-specificity protein kinases that play a role in a mitogen activated protein kinase cascade that controls cell growth and differentiation (1-3). Activation of MEK1 and MEK2 occurs through phosphorylation of Ser217 and Ser221 within the activation loop of subdomain VIII by Raf-like molecules. MEK1/2 is activated by a wide variety of growth factors and cytokines, and through membrane depolarization and calcium influx (1-4). Constitutively active MEK1/2 can promote transformation of NIH/3T3 cells and differentiation of PC-12 cells (4). MEK activates p44 and p42 MAP kinase by phosphorylating both threonine and tyrosine residues at sites located within the activation loop of kinase subdomain VIII.

PD98059 is a highly selective in vitro inhibitor of MEK1 activation and the MAP kinase cascade (1-4). The PD98059 flavonoid binds to inactive forms of MEK1 and prevents activation by upstream activators, such as c-Raf (3). PD98059 inhibits MEK1 and MEK2 activation with IC₅₀ values of 4 µM and 50 µM, respectively (1-3). Research studies demonstrate that PD98059 does not inhibit activation of other highly related dual-specificity protein kinases or the activity of more than 18 Ser/Thr protein kinases (3). Western blot analyses indicate that PD98059 does not inhibit activation of MKK3 or SEK (MKK4) at concentrations up to 100 µM, and does not inhibit MKK6 or related family members.