Activation of Mitogen-activated Protein (MAP) Kinase Pathway by Pervanadate, a Potent Inhibitor of Tyrosine Phosphatases

• Published in: The Journal of biological chemistry Vol. 271; no. 36; pp. 22251 - 22255
• Main Authors: Zhao, Z, Tan, Z, Diltz, C D, You, M, Fischer, E H
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 06-09-1996
• Subjects: Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Dose-Response Relationship, Drug; Enzyme Activation; HeLa Cells; Humans; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Protein Tyrosine Phosphatases - antagonists & inhibitors; Protein Tyrosine Phosphatases - metabolism; Time Factors; Vanadates - pharmacology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.271.36.22251

Rapid tyrosine phosphorylation of key cellular proteins is a crucial event in signal transduction. The regulatory role of
protein-tyrosine phosphatases (PTPs) in this process was explored by studying the effects of a powerful PTP inhibitor, pervanadate,
on the activation of the mitogen-activated protein (MAP) kinase cascade. Treatment of HeLa cells with pervanadate resulted
in a marked inhibition of PTP activity, accompanied by a drastic increase in tyrosine phosphorylation of cellular proteins.
The increased tyrosine phosphorylation coincided with the activation of the MAP kinase cascade as indicated by enzymatic activity
assays of MEK (MAP kinase/ERK-kinase) and MAP kinase and gel mobility shift analyses of Raf-1 and MAP kinase. The activation
was sustained but reversible. Upon removal of pervanadate, both tyrosine phosphorylation and MAP kinase activation declined
to basal levels. Therefore, inhibition of PTP activity is sufficient per se to initiate a complete MAP kinase activation program.