Abstract
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.
Highlights
Rapid tyrosine phosphorylation of key cellular proteins is a crucial event in signal transduction
This study demonstrates that inactivation of protein-tyrosine phosphatases (PTPs) by pervanadate increases tyrosine phosphorylation of proteins that are regulated by tyrosine phosphorylation and lead to activation of the whole mitogen-activated protein (MAP) kinase cascade
Pervanadate Inhibits PTP Activity and Stimulates Protein Tyrosine Phosphorylation and Activation of MEK and MAP Kinase—HeLa cells were treated with vanadate, H2O2, pervanadate, Epidermal growth factor (EGF), and Phorbol 12-myristate 13-acetate (PMA)
Summary
22251–22255, 1996 Printed in U.S.A. Activation of Mitogen-activated Protein (MAP) Kinase Pathway by Pervanadate, a Potent Inhibitor of Tyrosine Phosphatases*. Among various PTP inhibitors, vanadate and its derivative, pervanadate, have been found widespread use as inhibitors of PTPs [2] These compounds cause increases in tyrosine phosphorylation and various cell signaling responses. Despite intense investigation in this area, effects of these PTP inhibitors on MAP kinase activation, a pleiotropic signaling pathway playing crucial role in cell proliferation, differentiation, and transformation, have not been demonstrated. Studying the role of PTP inhibitors in this process is of general significance in understanding the function of PTPs. This study demonstrates that inactivation of PTPs by pervanadate increases tyrosine phosphorylation of proteins that are regulated by tyrosine phosphorylation and lead to activation of the whole MAP kinase cascade
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