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.
    Journal of Neuroscience Research 02/2015; 93(8). DOI:10.1002/jnr.23576 · 2.59 Impact Factor
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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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    Frontiers in Aging Neuroscience 09/2014; 6:232. DOI:10.3389/fnagi.2014.00232 · 4.00 Impact Factor
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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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