Protein Phosphatase 2A Inhibitors, I1PP2A and I2PP2A, Associate with and Modify the Substrate Specificity of Protein Phosphatase 1

Katayose, Yoshihisa; Li, Mei; Al-Murrani, Samer W.K.; Shenolikar, Shirish; Damuni, Zahi

doi:10.1074/jbc.275.13.9209

Cited by 51 publications

(26 citation statements)

References 51 publications

(93 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Other interacting proteins have also been found to have dual functions depending on their partner. Inhibitor 1/PP2A and inhibitor 2/PP2A are two proteins known to inhibit PP2A that can also stimulate PP1 activity in vitro [unlike inhibitor-1 (I1), which is a PP1 inhibitor] [27]. In addition to anchoring proteins, specific endogenous activators/inhibitors exist that contribute to regulating phosphatase activity.…”

Section: Serine/threonine Phosphatasesmentioning

confidence: 99%

Protein phosphatases and their potential implications in neuroprotective processes

Gee

Mansuy

2005

CMLS, Cell. Mol. Life Sci.

View full text Add to dashboard Cite

Several neurological disorders such as stroke, amyotrophic lateral sclerosis and epilepsy result from excitotoxic events and are accompanied by neuronal cell death. These processes engage multiple signalling pathways and recruit numerous molecular components, in particular several families of protein kinases and protein phosphatases. While many investigations have examined the importance of protein kinases in excitotoxicity, protein phosphatases have not been well studied in this context. However, recent advances in understanding the functions of protein phosphatases have suggested that they may play a neuroprotective role. In this review, we summarize some of the recent findings that illustrate the pleiotropic and complex functions of tyrosine and serine/threonine protein phosphatases in the cascade of events leading to neuronal cell death, and highlight their potential intervention in limiting the extent of neuronal death.

show abstract

Section: Serine/threonine Phosphatasesmentioning

confidence: 99%

Protein phosphatases and their potential implications in neuroprotective processes

Gee

Mansuy

2005

CMLS, Cell. Mol. Life Sci.

View full text Add to dashboard Cite

show abstract

“…Other proteins such as G-substrate and dopamine and cAMP-regulated phosphoprotein Mr 32000 (DARPP-32), which exhibit considerable sequence overlap with I1, also inhibit PP1 [6]. Although the most thoroughly researched accessory proteins are inhibitory, two proteins which inhibit the related phosphatase PP2A, I1 (PP2A) and I2 (PP2A), actually increase the catalytic activity of PP1 in vitro [7]. In neural tissue, the sequestration of PP1 to structures such as the postsynaptic density (PSD), a multi-protein complex found at synapses and that contains hundreds of signal transduction molecules, is particularly important for the functioning of many signalling proteins.…”

Section: Endogenous Regulation Of Pp1 Activitymentioning

confidence: 99%

The role of protein phosphatase-1 in the modulation of synaptic and structural plasticity

MUNTON¹

2004

FEBS Letters

View full text Add to dashboard Cite

Synaptic plasticity is a phenomenon contributing to changes in the efficacy of neuronal transmission. These changes are widely believed to be a major cellular basis for learning and memory. Protein phosphorylation is a key biochemical process involved in synaptic plasticity that operates through a tight balance between the action of protein kinases and protein phosphatases (PPs). Although the majority of research in this field has concentrated primarily on protein kinases, the significant role of PPs is becoming increasingly apparent. This review examines one such phosphatase, PP1, and highlights recent advances in the understanding of its intervention in synaptic and structural plasticity and the mechanisms of learning and memory.

show abstract

“…The phosphoprotein SET, a highly specific inhibitor of PP2A (37), was tested as an attractive candidate for such a factor. SET exerts other activities, including inhibition of cell cycle (39,40), promoting expression of the gene for P450c17 in mouse testis MA-10 Leydig cells (29,41) and modifying the substrate specificity of PP1 (42). SET (7.8 nM) inhibited the activity of PP2A but not PP4 using phosphorylated NCI-H295A microsomal proteins as substrate in vitro (Fig.…”

Section: Regulation Of 1720 Lyase Activity By Phosphatases In Nci-mentioning

confidence: 99%

Protein Phosphatase 2A and Phosphoprotein SET Regulate Androgen Production by P450c17

Pandey¹,

Mellon²,

Miller³

2003

Journal of Biological Chemistry

133

View full text Add to dashboard Cite

Cytochrome P450c17 catalyzes 17␣-hydroxylation needed for cortisol synthesis and 17,20 lyase activity needed to produce sex steroids. Serine phosphorylation of P450c17 specifically increases 17,20 lyase activity, but the physiological factors regulating this effect remain unknown. Treating human adrenal NCI-H295A cells with the phosphatase inhibitors okadaic acid, fostriecin, and cantharidin increased 17,20 lyase activity, suggesting involvement of protein phosphatase 2A (PP2A) or 4 (PP4). PP2A but not PP4 inhibited 17,20 lyase activity in microsomes from cultured cells, but neither affected 17␣-hydroxylation. Inhibition of 17,20 lyase activity by PP2A was concentration-dependent, could be inhibited by okadaic acid, and was restored by endogenous protein kinases. PP2A but not PP4 coimmunoprecipitated with P450c17, and suppression of PP2A by small interfering RNA increased 17,20 lyase activity. Phosphoprotein SET found in adrenals inhibited PP2A, but not PP4, and fostered 17,20 lyase activity. The identification of PP2A and SET as post-translational regulators of androgen biosynthesis suggests potential additional mechanisms contributing to adrenarche and hyperandrogenic disorders such as polycystic ovary syndrome.Steroid hormones are synthesized by a set of pathways that begin with the conversion of cholesterol to pregnenolone by mitochondrial cytochrome P450scc, the quantitative regulator of steroidogenesis. Pregnenolone can then be directed to one of three principal pathways by microsomal P450c17, the qualitative regulator of steroidogenesis, which catalyzes both 17␣-hydroxylase and 17,20 lyase activities (1-4) (Fig. 1). In the absence of P450c17, e.g. in adrenal zona glomerulosa and ovarian granulosa cells, pregnenolone is converted to 17-desoxy, C21 steroids including progesterone, corticosterone, and aldosterone. In the presence of the 17␣-hydroxylase activity of P450c17, the adrenal zona fasciculata produces C21 17␣-hydroxy steroids including the glucocorticoid cortisol. When both 17␣-hydroxylase and 17,20 lyase activities are present, the adrenal zona reticularis and gonads produce the C19 17-ketosteroid dehydroepiandrosterone (DHEA), 1 which is the precursor of androgens and estrogens.The ratio of the 17␣-hydroxylase to 17,20 lyase activities of human P450c17 is developmentally regulated. Adjusted for body size, the human adrenal produces nearly constant amounts of cortisol throughout life, indicating relatively constant 17␣-hydroxylase activity (5). By contrast, the production of DHEA is minimal in childhood, rises 100-fold to levels that exceed the production of cortisol in young adulthood, and then gradually decreases with advancing age (6). The mechanisms by which human adrenal C19 steroid synthesis is turned on (adrenarche) and turned off (adrenopause) remain unclear. Recent clinical observations suggest a link between premature exaggerated adrenarche and the polycystic ovary syndrome (7-10). Adrenarche is difficult to study because it occurs only in higher primates (10 -12), and no cellular model e...

show abstract

Protein Phosphatase 2A Inhibitors, I1PP2A and I2PP2A, Associate with and Modify the Substrate Specificity of Protein Phosphatase 1

Abstract: Recombinant

Cited by 51 publications

References 51 publications

Protein phosphatases and their potential implications in neuroprotective processes

Protein phosphatases and their potential implications in neuroprotective processes

The role of protein phosphatase-1 in the modulation of synaptic and structural plasticity

Protein Phosphatase 2A and Phosphoprotein SET Regulate Androgen Production by P450c17

Contact Info

Product

Resources

About