scholarly journals Amyloid-directed phosphatase activation

2019 ◽  
Vol 20 (10) ◽  
pp. 571-571
Author(s):  
Paulina Strzyz
Keyword(s):  
Phosphatase Activation

Protein kinase A acts at multiple points to inhibit Xenopus oocyte maturation

1994 ◽  
Vol 14 (7) ◽  
pp. 4419-4426
Author(s):  
W Matten ◽  
I Daar ◽  
G F Vande Woude
Keyword(s):  
Protein Kinase ◽  
Xenopus Oocytes ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Mobility Shift ◽  
Dependent Protein Kinase ◽  
Multiple Points ◽  
Mitogen Activated Protein ◽  
Dependent Protein ◽  
Phosphatase Activation

In Xenopus oocytes, initiation of maturation is dependent on reduction of cyclic AMP-dependent protein kinase (PKA) activity and the synthesis of the mos proto-oncogene product. Mos is required during meiosis I for the activation of both maturation-promoting factor (MPF) and mitogen-activated protein kinase (MAPK). Here we show that injection of the catalytic subunit of PKA (PKAc) prevented progesterone-induced synthesis of endogenous Mos as well as downstream MPF and MAPK activation. However, PKAc did not prevent injected soluble Mos product from activating MAPK. While MAPK is activated during Mos-PKAc coinjection, attendant MPF activation is blocked. Additionally, PKAc caused a potent block in the electrophoretic mobility shift of cdc25 that is associated with phosphatase activation. This inhibition of cdc25 activity was not reversed by progesterone, Mos, or MPF. We conclude that PKAc acts as a negative regulator at several points in meiotic maturation by preventing both Mos translation and MPF activation.

scholarly journals A MultiTEP platform-based epitope vaccine targeting the phosphatase activating domain (PAD) of tau: therapeutic efficacy in PS19 mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Armine Hovakimyan ◽  
Tatevik Antonyan ◽  
Sepideh Kiani Shabestari ◽  
Olga Svystun ◽  
Gor Chailyan ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Therapeutic Efficacy ◽  
Cell Epitope ◽  
Antibody Responses ◽  
Age Related ◽  
Promising Target ◽  
B Cell Epitope ◽  
Effective Reduction ◽  
Phosphatase Activation ◽  
Tau Polymerization

Abstract Pathological tau correlates well with cognitive impairments in Alzheimer’s disease (AD) patients and therefore represents a promising target for immunotherapy. Targeting an appropriate B cell epitope in pathological tau could in theory produce an effective reduction of pathology without disrupting the function of normal native tau. Recent data demonstrate that the N-terminal region of tau (aa 2-18), termed the “phosphatase activation domain (PAD)”, is hidden within native Tau in a ‘paperclip’-like conformation. Conversely, PAD is exposed in pathological tau and plays an essential role in the inhibition of fast axonal transport and tau polymerization. Thus, we hypothesized that anti-tau2-18 antibodies may safely and specifically reduce pathological tau and prevent further aggregation, which in turn would neutralize tau toxicity. Therefore, we evaluated the immunogenicity and therapeutic efficacy of our MultiTEP platform-based vaccine targeting tau2-18 formulated with AdvaxCpG adjuvant (AV-1980R/A) in PS19 tau transgenic mice. The AV-1980R/A induced extremely high antibody responses and the resulting sera recognized neurofibrillary tangles and plaque-associated dystrophic neurites in AD brain sections. In addition, under non-denaturing conditions AV-1980R/A sera preferentially recognized AD-associated tau. Importantly, vaccination also prevented age-related motor and cognitive deficits in PS19 mice and significantly reduced insoluble total and phosphorylated tau species. Taken together, these findings suggest that predominantly targeting misfolded tau with AV-1980R/A could represent an effective strategy for AD immunotherapy.

ANG II AT1 and AT2 receptors both inhibit bFGF-induced proliferation of bovine adrenocortical cells

1997 ◽  
Vol 273 (4) ◽  
pp. C1324-C1334 ◽  
Author(s):  
Panagiotis Liakos ◽  
Nicolas Bourmeyster ◽  
Geneviève Defaye ◽  
Edmond M. Chambaz ◽  
Serge P. Bottari
Keyword(s):  
Tyrosine Phosphatase ◽  
Prostaglandin E ◽  
Receptor Subtypes ◽  
Cyclin D ◽  
Ang Ii ◽  
Inhibition Of Proliferation ◽  
Phosphatase Inhibitors ◽  
Inhibition Of Growth ◽  
Growth Promoting ◽  
Phosphatase Activation

Angiotensin II (ANG II) has long been known for its pressor and growth-promoting effects, which are both mediated by the AT1 receptor. By contrast, the AT2 receptor has recently been reported to mediate inhibition of proliferation through as yet undefined mechanisms. We report here that in bovine adrenal fasciculata cells ANG II by itself does not affect growth but inhibits basic fibroblast growth factor (bFGF)-induced DNA synthesis and blocks the cells in G1 phase. Consistent with this, ANG II inhibits cyclin D1 expression and cyclin D1-associated kinase activity. The antimitogenic effect of ANG II is partly mimicked by the AT2-selective agonist CGP-42112. It is also blocked partly and in an additive fashion by the AT1- and AT2-selective antagonists losartan and PD-123319, indicating the contribution of both receptor subtypes to this response. AT1-dependent antiproliferation is selectively blocked by the cyclooxygenase inhibitor indomethacin and restored by prostaglandin E2, whereas AT2-receptor-mediated inhibition of growth is suppressed by the tyrosine phosphatase inhibitors orthovanadate and bpV(pic). Both pathways are, however, pertussis toxin sensitive. We hypothesize that, in fasciculata cells, the AT1 receptor inhibits bFGF-induced proliferation by stimulating prostaglandin synthesis, whereas the AT2 receptor mediates its effect through a pathway that requires protein tyrosine phosphatase activation.

scholarly journals Inhibition of protein phosphatase 1 reverses alcohol-induced ciliary dysfunction

2015 ◽  
Vol 308 (6) ◽  
pp. L577-L585 ◽  
Author(s):  
Michael E. Price ◽  
Jacqueline A. Pavlik ◽  
Joseph H. Sisson ◽  
Todd A. Wyatt
Keyword(s):  
Protein Phosphatase ◽  
Mucociliary Clearance ◽  
Specific Inhibitor ◽  
Alcohol Exposure ◽  
Inhibitory Effect ◽  
Regulatory Proteins ◽  
Protein Phosphatase 1 ◽  
Tissue Cell ◽  
Inhaled Particles ◽  
Phosphatase Activation

Airway mucociliary clearance is a first-line defense of the lung against inhaled particles and debris. Among individuals with alcohol use disorders, there is an increase in lung diseases. We previously identified that prolonged alcohol exposure impairs mucociliary clearance, known as alcohol-induced ciliary dysfunction (AICD). Cilia-localized enzymes, known as the ciliary metabolon, are key to the pathogenesis of AICD. In AICD, cyclic nucleotide-dependent ciliary kinases, which modulate phosphorylation to regulate cilia beat, are desensitized. We hypothesized that alcohol activates cilia-associated protein phosphatase 1 (PP1) activity, driving phosphorylation changes of cilia motility regulatory proteins. To test this hypothesis we identified the effects of prolonged alcohol exposure on phosphatase activity, cilia beat, and kinase responsiveness and cilia-associated phosphorylation targets when stimulated by β-agonist or cAMP. Prolonged alcohol activated PP1 and blocked cAMP-dependent cilia beat and protein kinase A (PKA) responsiveness and phosphorylation of a 29-kDa substrate of PKA. Importantly, prolonged alcohol-induced phosphatase activation was inhibited by the PP1 specific inhibitor, inhibitor-2 (I-2), restoring cAMP-stimulated cilia beat and PKA responsiveness and phosphorylation of the 29-kDa substrate. The I-2 inhibitory effect persisted in tissue, cell, and isolated cilia-organelle models, highlighting the association of ciliary metabolon-localized enzymes to AICD. Prolonged alcohol exposure drives ciliary metabolon-localized PP1 activation. PP1 activation modifies phosphorylation of a 29-kDa protein related to PKA activity. These data reinforce our previous findings that alcohol is acting at the level of the ciliary metabolon to cause ciliary dysfunction and identifies PP1 as a therapeutic target to prevent or reverse AICD.

Wortmannin inhibits insulin-stimulated activation of protein phosphatase 1 in rat cardiomyocytes

1999 ◽  
Vol 276 (5) ◽  
pp. H1520-H1526 ◽  
Author(s):  
Jane P. de Luca ◽  
Alice K. Garnache ◽  
Jill Rulfs ◽  
Thomas B. Miller
Keyword(s):  
Protein Phosphatase ◽  
Glycogen Synthase ◽  
Protein Phosphatase 1 ◽  
Rat Cardiomyocytes ◽  
Major Function ◽  
Pi3k Inhibitors ◽  
Protein Levels ◽  
Pi3k Activity ◽  
Insulin Dependent ◽  
Phosphatase Activation

A major function of insulin in target tissues is the activation of glycogen synthase. Phosphatidylinositol 3-kinase (PI3K) has been implicated in the insulin-induced activation of glycogen synthase, although the true function of this enzyme remains unclear. Data presented here demonstrate that the PI3K inhibitors wortmannin and LY-294002 block the insulin-stimulated activation of protein phosphatase 1 (PP1) in rat ventricular cardiomyocytes. This loss of phosphatase activation mimics that seen in diabetic cardiomyocytes, in which insulin stimulation fails to activate both PP1 and glycogen synthase. Interestingly, in diabetic cells, insulin stimulated PI3K activity to 300% of that in untreated controls, whereas this activity was increased by only 77% in normal cells. PI3K protein levels, however, were similar in normal and diabetic cells. Our results indicate that PI3K is involved in the stimulation of glycogen synthase activity by insulin through the regulation of PP1. The inability of insulin to stimulate phosphatase activity in diabetic cells, despite a significant increase in PI3K activity, suggests a defect in the insulin signaling pathway that contributes to the pathology of insulin-dependent diabetes.

scholarly journals t-SNARE Phosphorylation Regulates Endocytosis in Yeast

2002 ◽  
Vol 13 (5) ◽  
pp. 1594-1607 ◽  
Author(s):  
Sangiliyandi Gurunathan ◽  
Michael Marash ◽  
Adina Weinberger ◽  
Jeffrey E. Gerst
Keyword(s):  
Protein Phosphatase ◽  
Normal Growth ◽  
Gene Inactivation ◽  
Temperature Sensitive ◽  
Temperature Sensitive Mutation ◽  
Phosphatase Activation ◽  
Mating Factor ◽  
In Cells

Earlier we demonstrated that activation of a ceramide-activated protein phosphatase (CAPP) conferred normal growth and secretion to yeast lacking their complement of exocytic v-SNAREs (Snc1,2) or bearing a temperature-sensitive mutation in an exocytic t-SNARE (Sso2). CAPP activation led to Sso dephosphorylation and enhanced the assembly of t-SNAREs into functional complexes. Thus, exocytosis in yeast is modulated by t-SNARE phosphorylation. Here, we show that endocytic defects in cells lacking the v- and t-SNAREs involved in endocytosis are also rescued by CAPP activation. Yeast lacking the Tlg1 or Tlg2 t-SNAREs, the Snc v-SNAREs, or both, undergo endocytosis after phosphatase activation. CAPP activation correlated with restored uptake of FM4-64 to the vacuole, the uptake and degradation of the Ste2 receptor after mating factor treatment, and the dephosphorylation and assembly of Tlg1,2 into SNARE complexes. Activation of the phosphatase by treatment with C2-ceramide,VBM/ELO gene inactivation, or by the overexpression of SIT4 was sufficient to confer rescue. Finally, we found that mutation of single PKA sites in Tlg1 (Ser31 to Ala31) or Tlg2 (Ser90 to Ala90) was sufficient to restore endocytosis, but not exocytosis, to snc cells. These results suggest that endocytosis is also modulated by t-SNARE phosphorylation in vivo.

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