Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thiol proteins are important in cellular antioxidant defenses and redox signalling. It is postulated that reactive oxidants cause selective thiol oxidation, but relative sensitivities of different cell proteins and critical targets are not well characterized. We exposed Jurkat cells to H2O2 for 10 min and measured changes in reversibly oxidized proteins by labelling with iodoacetamidofluorescein and two-dimensional electrophoresis. At 200 microM H2O2, which caused activation of the MAP (mitogen-activated protein) kinase ERK (extracellular-signal-regulated kinase), growth arrest and apoptosis, relatively few changes were seen. A total of 28 spots were reversibly oxidized (increased labelling intensity) and 24 decreased. The latter included isoforms of peroxiredoxins 1 and 2, which were irreversibly oxidized. Oxidation of GAPDH (glyceraldehyde-3-phosphate dehydrogenase) was striking, and other affected proteins included glutathione S-transferase P1-1, enolase, a regulatory subunit of protein kinase A, annexin VI, the mitotic checkpoint serine/threonine-protein kinase BUB1beta, HSP90beta (heat-shock protein 90beta) and proteosome components. At 20 microM H2O2, changes were fewer, but GAPDH and peroxiredoxin 2 were still modified. Dinitrochlorobenzene treatment, which inhibited cellular thioredoxin reductase and partially depleted GSH, caused reversible oxidation of several proteins, including thioredoxin 1 and peroxiredoxins 1 and 2. Most changes were distinct from those with H2O2, and changes with H2O2 were scarcely enhanced by dinitrochlorobenzene. Relatively few proteins, including deoxycytidine kinase, nucleoside diphosphate kinase and a proteosome activator subunit, responded only to the combined treatment. Thus most of the effects of H2O2 were not linked to thioredoxin oxidation. Our study has identified peroxiredoxin 2 and GAPDH as two of the most oxidant-sensitive cell proteins and has highlighted how readily peroxiredoxins undergo irreversible oxidation.
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PMID:Proteomic detection of hydrogen peroxide-sensitive thiol proteins in Jurkat cells. 1580 6

The active oxygen species (AOS) that arise from normal metabolic processes are kept under tight control by various antioxidant mechanisms. AOS are important signal molecules that regulate many physiological processes, including environmental stress responses. In this work, we have investigated the effect of lowered cytosolic ascorbate peroxidase (APX) activity in transgenic tobacco BY-2 cells, using two transformed BY-2 cell lines, cAPX-S2 and cAPX-S3, resulting from co-suppression by expression of Arabidopsis APX1 cDNA under the cauliflower mosaic virus (CaMV) 35S promoter. cAPX-S2 and cAPX-S3 possessed 50 and 75% lower cytosolic APX activity, respectively, compared with that in the untransformed cells. Chemical fluorescence analysis indicated that the AOS levels were markedly higher in the two APX-suppressed cell lines than in the wild-type cells. However, there were no substantial differences in the activity levels of the various other antioxidant enzymes. Interestingly, the APX-suppressed cells showed different responses and tolerances to environmental stresses, such as heat and salinity. Suppression subtractive hybridization revealed that several heat- and salt stress-inducible genes were up-regulated in cAPX-S3 cells. HSP70, DnaJ-like protein and purple acid phosphatase were among the constitutively induced genes. An in-gel kinase assay suggested that a mitogen-activated protein (MAP) kinase of approximately 46 kDa was predominantly active in the APX-suppressed cells, and transcript levels of both nicotiana protein kinase 1 (NPK1) and nucleoside diphosphate kinase 2 (NDPK2) were up-regulated. These data suggest the possibility that MAP kinase cascades are activated by subtle imbalances in the homeostasis of the cellular redox status caused by lowered cytosolic APX activity.
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PMID:Acclimation to diverse environmental stresses caused by a suppression of cytosolic ascorbate peroxidase in tobacco BY-2 cells. 1591 70

Cystic fibrosis (CF) results from mutations within the cystic fibrosis transmembrane-conductance regulator (CFTR) protein. The AMP-activated protein kinase (AMPK) is a heterotrimer composed of different isoforms of the alphabetagamma subunits, where the alpha1 catalytic subunit binds CFTR. Nucleoside diphosphate kinase (NDPK, NM23/awd) converts nucleoside diphosphates to nucleoside triphosphates but also acts as a protein kinase. We recently showed that AMPK alpha1 binds NDPK-A in lung epithelial cytosol. Here we report that in the plasma membrane of human airway epithelial cells, NDPK-A and AMPK alpha1 associate with the plasma membrane via CFTR. We show that the regulatory domain of CFTR binds NDPK-A whereas AMPK gamma1 or gamma2 bind the first nucleotide binding domain (NBD1) and AMPK alpha1 binds the second (NBD2) of CFTR. We also show that NDPK-A specifically binds AMPK alpha1 and AMPK gamma2 subunits, thereby specifying the isozyme of AMPK heterotrimer that associates with CFTR at the membrane. Thus, the combined data provide novel insight into the subunit composition of the epithelial CFTR/AMPK/NDPK complex, such that: CFTR interacts specifically with AMPK alpha1, gamma2 and NDPK-A and not NDPK-B or AMPK gamma1.
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PMID:NDPK-A (but not NDPK-B) and AMPK alpha1 (but not AMPK alpha2) bind the cystic fibrosis transmembrane conductance regulator in epithelial cell membranes. 1646 5

Previously we elucidated the molecular interaction between the nucleoside diphosphate kinase A (NDPK-A)/AMP-activated protein kinase (AMPK) alpha1 complex, discovering a process we termed "substrate channeling." Here, we investigate the protein-protein interaction of the substrate channeling complex with the pleiotropic protein kinase, CK2 (formerly casein kinase 2). We show that CK2 is part of the NDPK-A/AMPK alpha1 complex under basal (background AMPK activity) conditions, binding directly to each of the complex components independently. We report that when S122 on NDPK-A is phosphorylated by AMPK alpha1 in vivo, (i.e., stimulation of AMPK using either metformin or phenformin) initiating the substrate channeling mechanism, the catalytic subunit of CK2 (CK2alpha) is expelled from the complex and translocates to bind NDPK-B, a closely related but independent isoform of NDPK. Thus, we find that the AMPK-dependent phospho-status of S122 on NDPK-A determines whether CK2alpha swaps partners between NDPK-A and NDPK-B. This is the first reported linkage between NDPK-A and NDPK-B via a phosphorylation pathway and could explain the complex biology of NDPK. This study also offers an explanation as to how CK2alpha exclusion mutations (S120A or S122D of NDPK-A) on NDPK-A might have implications in cancer biology and general cellular energy metabolism.
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PMID:Protein kinase CK2 acts as a signal molecule switching between the NDPK-A/AMPK alpha1 complex and NDPK-B. 1790 30

Nucleoside diphosphate kinase A (NDPK-A) regulates the alpha1 isoform of the AMP-activated protein kinase (AMPK alpha1) selectively, independent of [AMP] and surrounding [ATP], by a process termed substrate channelling. Here, we show, using a range of empirically validated biochemical techniques, that the muscle form (M-LDH or LDH-A) and the heart form (H-LDH or LDH-B) of lactate dehydrogenase are physically associated with the liver cytosolic substrate-channelling complex such that M-LDH associates with NDPK-A, AMPK alpha1 and casein kinase 2 (CK2), whereas H-LDH associates with local NDPK-B. We find that the species of LDH bound to the substrate-channelling complex regulates the in vivo enzymatic activities of both AMPK and CK2, and has a downstream effect on the phospho-status of acetyl CoA carboxylase, a key regulator of cellular fat metabolism known to be a part of the cytosolic substrate-channelling complex in vivo. We hypothesise that the regulatory presence of LDH in the complex couples the substrate-channelling mechanism to both the glycolytic and redox states of the cell, allowing for efficient sensing of cell metabolic status, interfacing with the substrate-channelling complex and regulating the enzymatic activities of AMPK and CK2, two critical protein kinases.
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PMID:M-LDH serves as a regulatory subunit of the cytosolic substrate-channelling complex in vivo. 1757 40

This review focuses on a newly discovered interaction between protein kinases involved in cellular energetics, a process that may be disturbed in cystic fibrosis for unknown reasons. I propose a new model where kinase-mediated cellular transmission of energy provides mechanistic insight to a latent role of the cystic fibrosis transmembrane conductance regulator (CFTR). I suggest that CFTR acts as a multi-kinase recruiter to the apical epithelial membrane. My group finds that, in the cytosol, two protein kinases involved in cell energy homeostasis, nucleoside diphosphate kinase (NDPK) and AMP-activated kinase (AMPK), bind one another. Preliminary data suggest that both can also bind CFTR (function unclear). The disrupted role of this CFTR-kinase complex as 'membrane transmitter to the cell' is proposed as an alternative paradigm to the conventional ion transport mediated and CFTR/chloride-centric view of cystic fibrosis pathogenesis. Chloride remains important, but instead, chloride-induced control of the phosphohistidine content of one kinase component (NDPK, via a multi-kinase complex that also includes a third kinase, CK2; formerly casein kinase 2). I suggest that this complex provides the necessary near-equilibrium conditions needed for efficient transmission of phosphate energy to proteins controlling cellular energetics. Crucially, a new role for CFTR as a kinase controller is proposed with ionic concentration acting as a signal. The model posits a regulatory control relay for energy sensing involving a cascade of protein kinases bound to CFTR.
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PMID:The cystic fibrosis transmembrane recruiter the alter ego of CFTR as a multi-kinase anchor. 1780 62

The NM23 family proteins are involved in a variety of biological processes including tumor metastasis, development, and differentiation; however, their functions in the regulation of cellular proliferation are poorly understood. We have investigated the role of one NM23 family protein, NM23H2, in the regulation of cellular proliferation directed by the extracellular signal regulated kinase (ERK) pathway. The activity of ERKs was enhanced by knockdown of endogenous NM23H2 and blocked by overexpression of NM23H2 in both NIH3T3 and HEK293 cells. Additionally, the epidermal growth factor (EGF)- and oncogenic Ras(G12R)-induced proliferation of both HEK293 and NIH3T3 cells was reduced by NM23H2 overexpression. Furthermore, activation of Raf-1, MEK and the ERKs by either EGF or Ras(G12R) was inhibited by NM23H2 overexpression. Together, our data indicate that NM23H2 is a negative regulator of cellular proliferation stimulated by EGF- and Ras-mediated activation of the ERK pathway.
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PMID:NM23H2 inhibits EGF- and Ras-induced proliferation of NIH3T3 cells by blocking the ERK pathway. 1902 60

nm23-H1 was found to diminish metastatic potential of carcinoma cell lines and therefore was placed in the group of metastatic suppressor genes. Its protein product has a function of a nucleoside diphosphate kinase (NDPK) as well as protein kinase and nuclease. Though it was found that Nm23-H1 is involved in many cellular processes, it is still not known how it promotes metastatic suppressor activity. Since the process of metastasis is dependent on adhesion properties of cells, the goal of our work was to describe the adhesion properties of CAL 27 cells (oral squamous cell carcinoma of the tongue) overexpressing FLAG/nm23-H1. In our experiments, cells overexpressing nm23-H1 show reduced migratory and invasive potential. Additionally, cells overexpressing nm23-H1 adhere stronger on substrates (collagen IV and fibronectin) and show more spread morphology than the control cells. Results obtained by EGF induction of migration revealed that the adhesion strength predetermined cell response to chemoattractant and that Nm23-H1, in this cell type, does not interfere with, EGF induced, Ras signaling pathway. These data contribute to the overall knowledge about nm23-H1 and its role in cell adhesion, migration, and invasion, especially in oral squamous cell carcinoma.
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PMID:Nm23-H1 promotes adhesion of CAL 27 cells in vitro. 1926 57

Nm23-H1 encodes nucleoside diphosphate kinase A (NDPK-A) and is known to have a metastasis suppressive activity in many tumor cells. However, it has many other functions as well. Recent studies have shown that the interacting proteins with Nm23-H1 which mediate the cell proliferation, may act as modulators of the metastasis suppressor activity. The interacting proteins with Nm23-H1 can be classified into 3 groups. The first group of proteins can be classified as upstream kinases of Nm23-H1 such as CKI and Aurora-A/STK15. The second group of proteins acts as downstream effectors for the regulation of specific gene transcriptions, GTP-binding protein functions, and signal transduction in Erk signal cascade. The third group of proteins can be classified as bi-directionally influencing binding partners of Nm23-H1. As a result, the interactions with Nm23-H1 and binding partners have implications in the biochemical characterization involved in metastasis and tumorigenesis.
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PMID:Regulators affecting the metastasis suppressor activity of Nm23-H1. 1937 84

Tissue transglutaminase (tgase2) is a multifunctional enzyme that crosslinks proteins but also acts as a G-protein, differential functions regulated by calcium and GTP. In the epithelial cell membrane, we show that manipulation of tgase2 function by monodansylcadaverine or retinoic acid (RA) alters the activity of a membrane-bound protein kinase, nucleoside diphosphate kinase (NDPK, nm23-H1/H2) that is known to control G-protein function. We find that NDPK function is abnormally low in cystic fibrosis but can be restored by RA treatment in vitro. Our data suggest that tgase2 is overexpressed in cystic fibrosis and affects NDPK function.
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PMID:Transglutaminase 2 and nucleoside diphosphate kinase activity are correlated in epithelial membranes and are abnormal in cystic fibrosis. 1961 46


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