Physiologic importance of protein phosphatase inhibitors

Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Frontiers in Bioscience (Impact Factor: 3.52). 10/1998; 3:D961-72.
Source: PubMed


Reversible protein phosphorylation is an important mode of regulation of cellular processes. While earlier studies focused on protein kinases, it is now apparent that protein phosphatases play an equally integral role in the control of cellular phosphoproteins. This review examines the role played by endogenous inhibitors of three major protein serine/threonine phosphatases, PP1, PP2A and PP2B in the control of cell physiology. The discussion highlights novel paradigms for signal transduction by protein phosphatase inhibitors that provide important avenues for signal amplification, the timing of physiological responses and cross-talk between distinct signal transduction pathways. New evidence also points to genetic abnormalities or altered expression of phosphatase inhibitors as potential mechanisms for human disease.Together, the data emphasize the physiological importance of protein phosphatase inhibitors and establish phosphatase regulation as a key feature of hormone signaling.

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    • "inhibitor I2PP1 , the acti - vation of PP1 in the GSK / I2PP1 / PP1 molecular complex ( Sakashita et al . , 2003 ) may be a key factor in disease development . Nevertheless , CDK5 is involved in the regulation of PP1 through the phosphorylation of inhibitor 1 ( I1PP1 ) and inhibitor 2 ( I2PP1 ) , both of which regulate activity by binding to PP1 ( Oliver et al . , 1998 ) . The dephosphorylated form of I2PP1 can bind to and inhibit PP1 ; CDK5 and GSK3 can phosphorylate and prevent the action of I2PP1 on PP1 ( Agarwal - Mawal and Paudel , 2001 ) . Unlike I2PP1 , the dephosphorylated form of I1PP1 remains inactive and does not perform any function on PP1 , but , when I1PP1 is phosphorylated by PKA , CDK5"
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    ABSTRACT: Inappropriate activation of cyclin-dependent kinase 5 (CDK5) resulting from proteolytic release of the activator fragment p25 from the membrane contributes to the formation of neurofibrillary tangles, β-amyloid (βA) aggregation, and chronic neurodegeneration. At 18 months of age, 3× Tg-AD mice were sacrificed after either 3 weeks (short term) or 1 year (long term) of CDK5 knockdown. In short-term-treated animals, CDK5 knockdown reversed βA aggregation in the hippocampi via inhibitory phosphorylation of glycogen synthase kinase 3β Ser9 and activation of phosphatase PP2A. In long-term-treated animals, CDK5 knockdown induced a persistent reduction in CDK5 and prevented βA aggregation, but the effect on amyloid precursor protein processing was reduced, suggesting that yearly booster therapy would be required. These findings further validate CDK5 as a target for preventing or blocking amyloidosis in older transgenic mice. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Full-text · Article · Feb 2015 · Journal of Neuroscience Research
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    • "CDK5 is involved in the regulation of PP1 through phosphorylation of inhibitor-1 (I1) and inhibitor-2 (I2), two regulators that bind to PP1 and inhibit its activity (Oliver and Shenolikar, 1998). The dephosphorylated form of I2 binds to and inhibits PP1; CDK5 and GSK3β phosphorylate PP1 at Thr72, preventing I2 from acting upon PP1 (Agarwal-Mawal and Paudel, 2001). "
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    ABSTRACT: Alzheimer's disease (AD) is the most common cause of dementia worldwide. One of the main pathological changes that occurs in AD is the intracellular accumulation of hyperphosphorylated Tau protein in neurons. Cyclin-dependent kinase 5 (CDK5) is one of the major kinases involved in Tau phosphorylation, directly phosphorylating various residues and simultaneously regulating various substrates such as kinases and phosphatases that influence Tau phosphorylation in a synergistic and antagonistic way. It remains unknown how the interaction between CDK5 and its substrates promotes Tau phosphorylation, and systemic approaches are needed that allow an analysis of all the proteins involved. In this review, the role of the CDK5 signaling pathway in Tau hyperphosphorylation is described, an in silico model of the CDK5 signaling pathway is presented. The relationship among these theoretical and computational models shows that the regulation of Tau phosphorylation by PP2A and glycogen synthase kinase 3β (GSK3β) is essential under basal conditions and also describes the leading role of CDK5 under excitotoxic conditions, where silencing of CDK5 can generate changes in these enzymes to reverse a pathological condition that simulates AD.
    Full-text · Article · Sep 2014 · Frontiers in Aging Neuroscience
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    • "Protein phosphorylation and dephosphorylation are central events in cell recognition of external and internal signals, leading to specific responses. While protein kinases transfer a phosphate group from ATP to a protein (i.e., phosphorylate), protein phosphatases catalyze the removal of phosphate groups from specific residues of proteins (i.e., dephosphorylate) [1] [2]. The balance between the antagonistic activities of protein kinases and phosphatases are responsible for many cellular functions, including metabolic pathways, cell-cell communication, proliferation, and gene transcription [3]. "
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    ABSTRACT: The interaction and survival of pathogens in hostile environments and in confrontation with host immune responses are important mechanisms for the establishment of infection. Ectophosphatases are enzymes localized at the plasma membrane of cells, and their active sites face the external medium rather than the cytoplasm. Once activated, these enzymes are able to hydrolyze phosphorylated substrates in the extracellular milieu. Several studies demonstrated the presence of surface-located ecto-phosphatases in a vast number of pathogenic organisms, including bacteria, protozoa, and fungi. Little is known about the role of ecto-phosphatases in host-pathogen interactions. The present paper provides an overview of recent findings related to the virulence induced by these surface molecules in protozoa and fungi.
    Full-text · Article · Apr 2011 · Journal of Parasitology Research
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