Description
PD 98059 is a noncompetitive inhibitor of the MAPK pathway. It prevents the activation of MEK by Raf or MEK kinase (a MAP3K) with an IC
50 value of 2-7 μM but does not inhibit Raf-activated MAP2K1. It inhibits Raf activation of MAP2K2 with an IC
50 value of 50 μM. PD 98059 also phosphorylates and activates AMP-activated protein kinase (AMPK) in a dose-dependent manner (EC
50 = 35 μM in HEK293 cells). It increases the ratios of ADP to ATP and AMP to ATP and increases phosphorylation of the AMPK target acetyl-CoA carboxylase (ACC).
Uses
PD 98059 is a selective inhibitor of MEK and blocker of MAPK.
Definition
ChEBI: A member of the class of monomethoxyflavones that is 3'-methoxyflavone bearing an additional amino substituent at position 2'
General Description
Selective, reversible, and cell-permeable inhibitor of MAP kinase kinase (MEK) that acts by inhibiting the activation of MAP kinase and subsequent phosphorylation of MAP kinase substrates. Pretreatment of PC-12 cells with PD 98059 completely blocks the 4-fold increase in MAP kinase activity produced by nerve growth factor (NGF; IC
50 = 2 μM); however, it has no effect on NGF-dependent tyrosine phosphorylation of the p140
trk receptor or its substrate Shc and does not block NGF-dependent activation of PI 3-kinase. Blocks LPS-induced activation of TNF-α gene expression. Inhibits cell growth and reverses the phenotype of
ras-transformed BALB3T3 mouse fibroblasts and rat kidney cells. A 5 mg/ml solution of PD 98059 (Cat. No.
513001) in anhydrous DMSO is also available.
Biological Activity
Specific inhibitor of mitogen-activated protein kinase kinase (MAPKK / MEK). Acts by binding to the inactivated form of MEK, thereby preventing its phosphorylation by cRAF or MEK kinase (IC 50 = 2-7 μ M). Inhibits cell growth and proliferation in acute myelogenous leukemia (AML) cell lines; causes G 1 arrest by blocking p53-dependent p21 induction. Also available as part of the MAPK Cascade Inhibitor Tocriset™ and MAPK Inhibitor Tocriset™ .
Biochem/physiol Actions
PD 98,059 is a flavonoid and specific inhibitor of mitogen-activated protein kinase kinase (MAPKK). In mice, PD 98,059 helps to block zymosan stimulated organ dysfunction syndrome and non-septic shock. It is known to inhibit in vitro hypertrophy. PD 98,059 also induces cartilage formation in mesenchymal stromal cells.
Background
The MAPK 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. 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. Constitutively active MEK1/2 can promote transformation of NIH/3T3 cells and differentiation of PC-12 cells. 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. The PD98059 flavonoid binds to inactive forms of MEK1 and prevents activation by upstream activators, such as c-Raf. PD98059 inhibits MEK1 and MEK2 activation with IC50 values of 4 µM and 50 µM, respectively. 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. Western blot analyses indicate that PD98059 does not inhibit activation of MKK3 or SEK at concentrations up to 100 µM, and does not inhibit MKK6 or related family members.
References
[1] D R ALESSI. PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo.[J]. The Journal of Biological Chemistry, 1995, 270 46: 27489-27494. DOI:
10.1074/jbc.270.46.27489[2] D T DUDLEY. A synthetic inhibitor of the mitogen-activated protein kinase cascade.[J]. Proceedings of the National Academy of Sciences of the United States of America, 1995, 92 17: 7686-7689. DOI:
10.1073/pnas.92.17.7686[3] HITOSHI HOTOKEZAKA. U0126 and PD98059, specific inhibitors of MEK, accelerate differentiation of RAW264.7 cells into osteoclast-like cells.[J]. The Journal of Biological Chemistry, 2002, 277 49: 47366-47372. DOI:
10.1074/jbc.m208284200[4] XIAOXIA QI. BMP4 supports self-renewal of embryonic stem cells by inhibiting mitogen-activated protein kinase pathways.[J]. Proceedings of the National Academy of Sciences of the United States of America, 2004, 101 16: 6027-6032. DOI:
10.1073/pnas.0401367101
