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  • Review Article
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Review Article

Small molecule inhibitors of dual specificity protein phosphatases

Oncogene volume 19, pages 6607–6612 (2000)Cite this article

Abstract

One hallmark of neoplasia is the deregulation of cell cycle control mechanisms, which is secondary to altered protein phosphorylation. Dual specificity protein phosphatases uniquely dephosphorylate both phosphoserines/threonines and phosphotyrosines on the same protein substrate. As a class they regulate intracellular signaling through the mitogen activated and stress activated kinases and govern cellular movement through G1/S and G2/M cell cycle checkpoints by affecting the activity of cyclin-dependent kinases. In particular, the Cdc25 phosphatases, which dephosphorylate cyclin-dependent kinases, are overexpressed in many human tumors and this increased expression is associated with a poor prognosis. In addition to expression levels, the intracellular activity of Cdc25 phosphatases is determined by their subcellular distribution and physical proximity to substrates. Small molecules that either inhibit the catalytic activity or alter the subcellular distribution of these dual specificity protein phosphatases could provide effective tools to interrogate the role of phosphorylation pathways and may afford new approaches to the management of cancer.

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Abbreviations

cdk:

cyclin dependent kinase

MAPK:

mitogen activated protein kinase

SAPK:

stress activated protein kinase

DSPases:

dual specificity phosphatases

ERK:

extracellular regulated kinase

IC50:

median inhibitory concentration

PTPases:

protein tyrosine phosphatases

PPases:

phosphoserine/phosphothreonine phosphatases

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Acknowledgements

The authors are supported in part by NIH Grant CA 43917, Army Breast Grant DAMD17-97-1-7229, NIH Training Grant T32 GM08424 (AP Ducruet) and the Fiske Drug Discovery Fund.

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Authors and Affiliations

  1. Department of Pharmacology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Katharine E Pestell, Alexander P Ducruet & John S Lazo

  2. Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Peter Wipf

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Pestell, K., Ducruet, A., Wipf, P. et al. Small molecule inhibitors of dual specificity protein phosphatases. Oncogene 19, 6607–6612 (2000). https://doi.org/10.1038/sj.onc.1204084

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