Nonhistone Nuclear Phosphoproteins
Lubomir S. Hnilica in Chromosomal Nonhistone Proteins, 2018
Phosphoprotein phosphatase is also present in nucleoli. Olson and Guetzow partially purified and characterized a nucleolus-associated phosphoprotein phosphatase from Novikoff hepatoma cells.141,142 In this regard, the phosphatase may be as important as the protein kinase in determining the overall pattern of phosphorylation. As discussed earlier, Kang et al.122 found that the profile of in vitro labeling was dependent on the type of divalent cation present. For example, protein B23 was not labeled in the presence of 5 mM MgCl2, but was labeled when 5 mM ZnCl2 was added to the system. The greatest overall uptake of 32P from [γ-32P] ATP into total proteins was also found in the presence of ZnCl2. It is interesting to note that Zn2+ was also a very effective inhibitor of phosphoprotein phosphatase.142 Differential metal ion effects may not have their basis at the kinase level, but certain metals may selectively inhibit phosphatases, thereby modulating the turnover of phosphate on specific proteins.
Cyclic Nucleotide Metabolism and Action During Senescence
Richard C. Adelman, George S. Roth in Endocrine and Neuroendocrine Mechanisms of Aging, 2017
Compared to the voluminous literature on protein kinases, very little work has been done towards characterizing phosphoprotein phosphatase(s) in different tissues. Only recently was it appreciated that what was previously considered to be a small, multifunctional enzyme actually exists in multiple forms of higher molecular weight.74,102,103 Again, as with cyclases, phosphodiesterases, and protein kinases, proteolysis confuses the picture obtained thus far. Rabbit muscle phosphorylase phosphatase can be degraded by a Ca2+-dependent protease from a less active, high molecular weight form to be more active, lower molecular weight forms.104 These phosphatases appear to be regulated differentially by protein inhibitors and activators,105,106 one inhibitor of which is active only after being phosphorylated by cyclic AMP-dependent protein kinase.107 The extent to which these effectors are present in various mammalian tissues is not known. Much additional basic work and a better understanding of the regulation and specificity of phosphoprotein phosphatases is needed before changes in their activities that may occur during senescene can be put into a meaningful, functional perspective.
Growth Factors
Stephen W. Carmichael, Susan L. Stoddard in The Adrenal Medulla 1986 - 1988, 2017
Rowland, Muller, Goldstein et al. (1987) developed a cell-free assay to detect and to characterize nerve growth factor-activated protein kinase activity. Cultured PC12 cells were briefly exposed to nerve growth factor and then extracts of these cells were assayed for phosphorylating activity. Nerve growth factor-treated cells showed 2 to 3 times more incorporation of phosphate than controls did. Activation did not occur if the growth factor was added directly to cell extracts. The increase in phosphorylation appeared to be due to regulation of a protein kinase rather than of a phosphoprotein phosphatase. The kinase appears to be a novel enzyme that Rowland et al. (1987) designated “kinase N.” A number of characteristics of kinase N were evaluated.
Inhibition of protein phosphatase-1 and -2A by ellagitannins: structure-inhibitory potency relationships and influences on cellular systems
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Zoltán Kónya, Bálint Bécsi, Andrea Kiss, Dániel Horváth, Mária Raics, Katalin E. Kövér, Beáta Lontay, Ferenc Erdődi
It is now well accepted that the phosphorylation of proteins is an important regulatory device in many cellular processes and it is regulated by not only the phosphorylating protein kinases but the dephosphorylating protein phosphatases as well1. Protein phosphatase-1 (PP1) and -2 A (PP2A) are two major representatives of the phosphoserine/threonine (P-Ser/Thr) specific enzymes and they are believed to be responsible for the dephosphorylation of more than 90% of P-Ser/Thr side chains in cellular phosphoproteins2. PP1 and PP2A occur in cells in many holoenzyme forms in which the catalytic subunits (PP1c and PP2Ac) are associated with distinct regulatory proteins. The three major isoforms (α, β/δ, and γ) of PP1c (PPP1CA, PPP1CB, and PPP1CG) may be complexed to close to 100 regulatory proteins which generally include a PP1c-interacting sequence termed the RVxF motif3. In the PP2A holoenzymes the core unit consists of PP2Ac (PPP2CA or PPP2CB) and a 65 kDa A subunit (termed PP2A-AC) and this dimer is associated with distinct classes of B subunit forming various trimer holoenzymes (PP2A-ABC)4.
Approaches for the discovery of drugs that target K Na 1.1 channels in KCNT1-associated epilepsy
Published in Expert Opinion on Drug Discovery, 2022
Barbara Miziak, Stanisław J Czuczwar
As already mentioned, the KCNT1 gene, is responsible for encoding sodium-activated potassium channels. Known mutations, altering the function of potassium channels, lead to the development of severe epilepsy and significant intellectual impairment [7,10,12]. The research data indicate that most of the disruption is localized to the extended cytoplasmic C-terminus of KNa 1.1 channels, resulting in increased potassium current [55]. One such example is the phosphorylation of this site by protein kinase C, which results in a rapid amplitude of potassium currents [10,55]. Studies indicate that this element is responsible for binding cytoplasmic signaling proteins, including Phactr1, which, by binding actin, recruits protein phosphatase 1 (PP1) to certain phosphoprotein substrates [55]. Other proteins have also been shown to be present, for example, FMRP, PSD95, CYFIP1, and TMEM16C, but their role is not yet as well understood [26,50,56]. Selected mutations on a KNa1.1 protein are presented in Figure 1.
Rutin hydrate ameliorates cadmium chloride-induced spatial memory loss and neural apoptosis in rats by enhancing levels of acetylcholine, inhibiting JNK and ERK1/2 activation and activating mTOR signalling
Published in Archives of Physiology and Biochemistry, 2018
Ghada A. Abdel-Aleem, Eman F. Khaleel
In the brain, oxidative stress can adversely affect survival signals and activate apoptotic death pathways. In the nervous system, activation of the c-Jun N-terminal kinase (JNK) and p38 signalling cascades have been shown to promote neuronal cell death (Davis 2000, Lei and Davis 2003, Rockwell et al. 2004, Chen et al. 2008, 2011a). Once activated, JNK can initiates apoptosis by various mechanisms that include at least phosphorylates of Bim-related members of the Bcl2 family induces Bax dependent apoptosis and by phosphorylation of BAD at ser 128 (Donovan et al. 2006). On the other hand, activation of extracellular signal-regulated kinase 1/2 (Erk1/2) of MAPKs signalling has double phases. Although it is primarily a survival signal in the brain and other tissues by phosphorylating BAD at ser 112 (Pearson et al. 2001, Cavanaugh 2004, Hetman and Gozdz 2004; Koh 2008), sustained activation of ERK1/2 initiate dephosphorylation of BAD at ser 112 to induce neural cell apoptosis (Alessandrini et al. 1999, Slevin et al. 2000, Zhu et al. 2002). However, MAP phosphatase 1 (MKP1) and serine/threonine protein phosphatase 2 A (PP2A) are the major phosphatases that negatively regulate all members of MAPKs (Liu et al. 2007). Also, in the neuronal tissue, mTOR/Akt/S6K1 has been widely recognized as a central controller for cell proliferation, growth, and survival (Jornsti and Houghton 2004). PTEN is the best well known negative inhibitor of mTOR/AKT/S6K1 survival pathway (Jornsti and Houghton 2004).
Related Knowledge Centers
- Adenosine Diphosphate
- Dephosphorylation
- Enzyme
- Phosphatase
- Phosphate
- Protein Kinase
- Substrate
- Post-Translational Modification
- Pseudokinase
- Adenosine Triphosphate