Abstract
With the recent clinical success of drugs targeting protein kinase activity, drug discovery efforts are focusing on the role of reversible protein phosphorylation in disease states. The activity of protein phosphatases, enzymes that oppose protein kinases, can also be manipulated to alter cellular signaling for therapeutic benefits. In this review, we present protein serine/threonine phosphatases as viable therapeutic targets, discussing past successes, current challenges, and future strategies for modulating phosphatase activity.
Footnotes
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This work was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant DK070787]; the National Institutes of Health National Institute of General Medicine [Grant GM051366]; the Vanderbilt-Ingram Cancer Center [Grant CA68485]; the Center for Molecular Neuroscience [Grant MH19732]; and the Vanderbilt Diabetes Research and Training Center [Grant DK20593].
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ABBREVIATIONS: CnA, calcineurin A subunit; CnB, calcineurin B subunit; CsA, cyclosporin A; Cyp, cyclophilin; eIF2α, eukaryotic initiation factor-2α; ER, endoplasmic reticulum; ERK, extracellular signal-regulated kinase; FCP, transcription factor II F-interacting carboxyl terminal domain phosphatase; FK506, tacrolimus; FKBP12, FK506 binding protein of 12 kDa; GADD34, growth arrest and DNA damage gene 34; HDAC, histone deacetylase; HSV, herpes simplex virus; IκB, inhibitor of κB; IKK, IκB kinase; INCA, inhibitors of NFAT-calcineurin association; MAP, mitogen-activated protein; MAPK, mitogen-activated protein kinase; MEK, MAPK/ERK kinase; NF-κB, nuclear factor-κB; NFAT, nuclear factor of activated T cells; Plk1, polo-like kinase 1; PP1, protein serine/threonine phosphatase 1; PP1c, catalytic subunit of PP1; PP2, protein serine/threonine phosphatase 2; PPM, magnesium/manganese-dependent protein phosphatase; PPP, phosphoprotein phosphatase; PSTP, protein serine/threonine phosphatase; PTP, protein tyrosine phosphatase; sal, salubrinal; SAR, structure-activity relationship; SV40, simian virus 40; TNF, tumor necrosis factor-α; TSA, trichostatin A.
- Received October 28, 2008.
- Accepted March 19, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
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