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Molecular Mechanisms of Brain Insulin Signaling 1
Published in André Kleinridders, Physiological Consequences of Brain Insulin Action, 2023
Simran Chopra, Robert Hauffe, André Kleinridders
As outlined above, the insulin signaling pathway is activated through a series of phosphorylation events. As protein phosphorylation is a reversible posttranslational modification, it represents a readily available site for fine-tuning the amplitude of the signaling response as well as a site for a negative feedback loop. Enzymatic dephosphorylation is carried out by phosphatases. In the case of the insulin signaling pathway, we can differentiate between two cases: (i) dephosphorylation of proteins in a negative feedback loop to stop the signaling cascade and (ii) inhibitory phosphorylation of proteins to limit the intensity of the cellular response to insulin (Figure 1.3).
Signal transduction and exercise
Published in Adam P. Sharples, James P. Morton, Henning Wackerhage, Molecular Exercise Physiology, 2022
Brendan Egan, Adam P. Sharples
Kinases typically are highly selective, which is based on their ability to recognise a particular amino acid motif on the phosphorylated protein. In contrast, phosphatases can usually dephosphorylate many proteins, but they target individual proteins for dephosphorylation by interacting with regulator subunits. For example, protein phosphatase-1 (PP1) interacts with the PP1 regulatory subunit 3A to specifically dephosphorylate muscle glycogen phosphorylase.
Breast Imaging with Positron Emission Tomography
Published in Raymond Taillefer, Iraj Khalkhali, Alan D. Waxman, Hans J. Biersack, Radionuclide Imaging of the Breast, 2021
Hans Bender, Holger Palmedo, Hans J. Biersack, Axel Schomburg
The intracellular accumulation of FDG is mediated by tissue-specific transporter mechanisms, which are partially insulin-dependent (myocard, muscle, fat tissue) and thereafter is phosphorylated by hexokinase. This phosphorylation to 2-FDG-6-phosphate results in a polar intermediate which does not cross the cell membrane and is trapped in the cells. Dephosphorylation occurs relatively slowly, particularly in cancer cells, which usually lack glucose-6-phosphatase (18-20).
PTPN22: structure, function, and developments in inhibitor discovery with applications for immunotherapy
Published in Expert Opinion on Drug Discovery, 2022
Brenson A. Jassim, Jianping Lin, Zhong-Yin Zhang
The mechanism of PTPN22 catalyzed dephosphorylation hinges on catalytic C227, which exists as a thiolate anion (pKa ~ 5) within the active site microenvironment [2]. Upon substrate binding to the P-loop, this nucleophilic cysteine attacks the phosphate group, initiating the dephosphorylation process. Phosphate group cleavage is paired with protonation of the substrate tyrosyl leaving group by the general acid D195. Hydrolysis of the phospho-enzyme intermediate is facilitated by Q274, which coordinates a water molecule near the phospho-enzyme intermediate. Activation of water by the now general base D195 regenerates free enzyme. Mutation of residues C227 and D195 produces catalytically dead enzyme incapable of turning over substrate and has been utilized as a substrate-trapping mutant [16]. The C-terminal region of PTPN22 harbors four poly-proline motifs (P1-P4) (Figure 1(a)), of which P1 has been shown to bind Csk, an important enzyme in T-cell signaling [12,17–19]. One mutational study suggested this interdomain region inhibits enzymatic activity via intramolecular interaction between the catalytic and interdomain regions [20]. Phosphorylation of PTPN22 S35 by protein kinase C (PKC) abolishes Lck Y394 dephosphorylation inside Jurkat cells by altering conformation of the specific insert [13]. Furthermore, PTPN22 may be regulated by reversible oxidation as one crystal structure shows presence of a disulfide bond between catalytic C227 and C129 [15].
Recent developments in Phos-tag electrophoresis for the analysis of phosphoproteins in proteomics
Published in Expert Review of Proteomics, 2022
Kimura et al. [82] proposed two methods to distinguish between phosphorylated and non-phosphorylated proteins. (i) A method of dephosphorylation using alkaline phosphatase that does not lose its enzyme activity even in an SDS-containing buffer solution before electrophoresis. (ii) A method in which both the protein sample and ethylenediaminetetraacetic acid solutions were added into one well and only the sample solution was added into another well of the Phos-tag SDS-PAGE gel to investigate the change in mobility. However, neither of them consistently gave good results. Okawara et al. [23] thought that 2-DE combining SDS-PAGE and Phos-tag SDS-PAGE, which Kinoshita et al. [14] first used, could solve the abovementioned problem. Subsequently, Okawara et al. improved the 2-DE method and developed Phos-tag diagonal electrophoresis by which phosphorylated and non-phosphorylated proteins can be distinguished clearly.
Network pharmacology and experimental investigation of Rhizoma polygonati extract targeted kinase with herbzyme activity for potent drug delivery
Published in Drug Delivery, 2021
Yingqiu Xie, Chengling Mu, Bexultan Kazybay, Qinglei Sun, Aidana Kutzhanova, Guldan Nazarbek, Na Xu, Lazzat Nurtay, Qian Wang, Amr Amin, Xugang Li
It is well-documented that kinases play essential roles in the regulation of metabolic processes of cells and are further involved in critical differentiation, proliferation, apoptosis, and cell development (Fabbro et al., 2015). Studies also show that phosphatases are involved in these phosphorylation–dephosphorylation processes along with kinases. It has been recognized that phosphatase might be essential in targeting cancer cell growth by disrupting kinase signaling pathways (Heinrich et al., 2018). Therefore, we hypothesize that nanozymatic phosphatase activity of RP might inhibit or disrupt the kinase signaling pathways, hence blocking cellular proliferation including cancer cells. It is additionally expected that RP ingredients could have a larger effect in combination with precision kinase inhibitor drugs against cancer cell growth. We further examined whether RP ingredients could have the potential to be used to inhibit cell growth in combination with kinase inhibitors which might be applied in treatments against other types of diseases in the future as well because many diseases are induced or related to kinase signaling for their progression.