Identification of para‐Substituted Benzoic Acid Derivatives as Potent Inhibitors of the Protein Phosphatase Slingshot
Kangshuai LiPeng XiaoDaolai ZhangXuben HouLin GeDuxiao YangHongda LiuDongfang HeXu ChenKe‐rui HanXiao‐yuan SongXiao YuHao FangJin‐Peng Sun
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Abstract Slingshot proteins form a small group of dual‐specific phosphatases that modulate cytoskeleton dynamics through dephosphorylation of cofilin and Lim kinases (LIMK). Small chemical compounds with Slingshot‐inhibiting activities have therapeutic potential against cancers or infectious diseases. However, only a few Slingshot inhibitors have been investigated and reported, and their cellular activities have not been examined. In this study, we identified two rhodanine‐scaffold‐based para ‐substituted benzoic acid derivatives as competitive Slingshot inhibitors. The top compound, ( Z )‐4‐((4‐((4‐oxo‐2‐thioxo‐3‐( o ‐tolyl)thiazolidin‐5‐ylidene)methyl)phenoxy)methyl)benzoic acid ( D3 ) had an inhibition constant ( K i ) of around 4 μ m and displayed selectivity over a panel of other phosphatases. Moreover, compound D3 inhibited cell migration and cofilin dephosphorylation after nerve growth factor (NGF) or angiotensin II stimulation. Therefore, our newly identified Slingshot inhibitors provide a starting point for developing Slingshot‐targeted therapies.Keywords:
Dephosphorylation
Benzoic acid
Cofilin
Dephosphorylation
Response regulator
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The phosphorylation and dephosphorylation reactions of the proteins of isolated rat liver nuclei were examined in the presence of ATP. It was shown that the plateau value of the phosphorus incorporation at high concentrations of ATP is the result of an equilibrium of phosphorylation and dephosphorylation. The data of 32P-labelling experiments and those of chemical determination of net change of phosphorus content were compared. The activity of an efficient protein phosphatase in rat liver nuclei is demonstrated. It was shown that the pool of protein-phosphorus in the nuclei is heterogeneous as regards its turnover rate. A protein-phosphorus fraction of high turnover dominates the picture of phosphorylation and dephosphorylation reactions when studied with [gamma-32P] ATP in vitro.
Dephosphorylation
Phosphorus-32
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Dephosphorylation
Cofilin
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To study rhodopsin (Rho) phosphorylation and dephosphorylation in Royal College of Surgeons (RCS) rat retina, specific antibodies toward major Rho phosphorylation sites in vivo, 334Ser or 338Ser, were prepared by immunization of authentic phosphorylated peptides in rabbit. Enzyme-linked immunosorbent assay identified that the raised antibodies exclusively recognized either the phosphorylated 334Ser or 338Ser site. In immunofluorescence labeling, both antibodies recognized photoreceptor outer segments in light-adapted retinas from Sprague-Dawley (SD), Brown-Norway (BN) and RCS rat. During dark adaptation, immunoreactivities toward phosphorylated 338Ser and 334Ser sites were diminished within several hours (0.2-2 h) in SD and BN rat retinas. However, those toward phosphorylated 338Ser and 334Ser sites were diminished within 4 to 7 days in RCS rat retinas. In vitro studies demonstrated decreased levels of both Rho phosphorylation and dephosphorylation reactions in RCS retinas. However, the dephosphorylation reaction was much more greatly affected than the phosphorylation reaction. Extremely prolonged survival of phosphorylated forms of Rho may contribute to persistent misregulation of phototransduction processes in retinal degeneration in RCS rat.
Dephosphorylation
Visual phototransduction
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Dephosphorylation
Hyperphosphorylation
Tau protein
Autophagy-related protein 13
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Objective To confirm the existence of dephosphorylation of cofilin in reestablishment of hepatocytic polarity.Methods Sandwich configuration was used to culture hepatocytes.Cell lysates was analyzed by immunoblotting using anti-P-cofilin and anti-cofilin antibodies to examine dephosphorylation of cofilin compared with a single collagen configuration.Results Sandwich-cultured hepatocytes reestablished cell polarity.The level of P-cofilin was reduced obviously in sandwich configuration cultured hepatocytes for 96h and one week contrasted to controls.Conclusion Cofilin dephosphorylation exists in the course of reestablishment of hepatocytic polarity.
Dephosphorylation
Cofilin
Polarity (international relations)
Cell polarity
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The deinhibitor protein, responsible for the decreased sensitivity of the ATP, Mg‐dependent protein phosphatase to inhibitor‐1 and the modulator protein, is inactivated by cyclic AMP‐dependent protein kinase and reactivated by dephosphorylation. The specificity of this reaction was tested with the ATP, Mg‐dependent phosphatase in its activated or spontaneously active form, four different forms of polycation‐stimulated phosphatases (PCS H , PCS M , PCS L and PCS C ) and calcineurin. Only the high ‐ M r , polycation‐stimulated protein phosphatase (PCS H ), but not its catalytic subunit (PCS C ), shows a high degree of specificity for the deinhibitor protein. Deinhibitor phosphatase activity of PCS H is affected neither by polycations nor by Mn ions.
Dephosphorylation
Protein phosphatase 1
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Enzymatic phosphorylation and dephosphorylation reactions were used to modify a genetically engineered variant of spider dragline silk. The ∼25 kDa protein was phosphorylated with cyclic AMP-dependent kinase and dephosphorylated with calf intestinal alkaline phosphatase. Phosphorylation inhibited β-sheet assembly of the protein and enhanced solubility to about 5 mg/mL in water, compared to about 20% of this level upon enzymatic dephosphorylation. The cyclability of the phosphorylation−dephosphorylation system was confirmed by MALDI with a model peptide. Kinetic studies conducted with [γ-32P]ATP illustrate that the phosphorylation reaction proceeds over 6 h. Secondary structure of the phosphorylated and dephosphorylated proteins was determined by CD and FTIR. The results illustrate that an enzymatic phosphorylation event can be used to control the solution structure of a protein like silk, which has a tendency to prematurely precipitate due to the formation of β-sheets.
Dephosphorylation
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Dephosphorylation
Phosphorylation cascade
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It has been reported that heparin coexists with the hyperphosphorylated tau in the brain of the patients of Alzheimer’s disease [7] . The effect of heparin on phosphorylation by NCLK and dephosphorylation by PP2B of tau protein has been studied. Heparin was observed to improve the phosphorylation of tau, to increase the formation of tau dimers and decrease tau monomers. The first order rate constants of dimer increasing and monomer decreasing were 2 88×10 -3 s -1 and 1 74×10 -3 s -1 respectively. PP2B catalyzed dephosphorylation of the phosphorylated tau by NCLK and heparin improved such dephosphorylation. It suggests that heparin may regulate the phosphorylation and dephosphorylation of tau.
Dephosphorylation
Tau protein
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