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)

Centrosome separation is regulated by balance of in situ protein kinase/phosphatase activities during the cell cycle. The mammalian NimA-related kinase Nek2 forms a complex with the catalytic subunit of protein phosphatase-1 (PP1C). This complex is located at centrosomes and has been implicated in regulation of the cycle of duplication and separation. Inhibitor-2 (Inh2) is an inhibitor protein specific for PP1C, and its expression level fluctuates during the cell cycle. Here we report cellular regulation of the Nek2.PP1C complex by Inh2. PP1C-binding segments of Nek2 were isolated by yeast two-hybrid screening using Inh2 bait. Inh2 indirectly associates with Nek2 via PP1C, which binds to both proteins, forming a bridged heterotrimeric complex. Double Ala mutation of the PP1C-binding site (KVHF) in Nek2 eliminated both PP1C and Inh2 interactions in both a yeast conjugation assay and an in vitro binding assay. The kinase activity of Nek2.PP1C was enhanced 2-fold by addition of recombinant Inh2, with EC(50) = 10 nm. Immunofluorescence showed concentration of endogenous Inh2 at centrosomes and in a region surrounding the centrosomes. Transient expression of wild-type Inh2 increased by 5-fold dispersed/split centrosomes in fibroblasts, mimicking the phenotype produced by overexpression of Nek2. Deletion of the Inh2 C-terminal domain yielded Inh2-(1-118), which failed to interact with or activate the Nek2.PP1C complex, suggesting that the C-terminal region of Inh2 is required for regulation of the Nek2.PP1C complex. Thus, Inh2 can enhance the kinase activity of the Nek2.PP1C complex via inhibition of phosphatase activity to initiate centrosome separation.
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PMID:Inhibitor-2 regulates protein phosphatase-1 complexed with NimA-related kinase to induce centrosome separation. 1222 Nov 3

The budding yeast Glc7 serine/threonine protein phosphatase-1 is regulated by Glc8, the yeast ortholog of mammalian phosphatase inhibitor-2. In this work, we demonstrated that similarly to inhibitor-2, Glc8 function is regulated by phosphorylation. The cyclin-dependent protein kinase, Pho85, in conjunction with the related cyclins Pcl6 and Pcl7 comprise the major Glc8 kinase in vivo and in vitro. Several glc7 mutations are dependent on the presence of Glc8 for viability. For example, glc7 alleles R121K, R142H, and R198D are lethal in combination with a glc8 deletion. We found that glc7-R121K is lethal in combination with a pho85 deletion. This finding indicates that Pho85 is the sole Glc8 kinase in vivo. Furthermore, glc7-R121K is also lethal when combined with deletions of pcl6, plc7, pcl8, and pcl10, indicating that these related cyclins redundantly activate Pho85 for Glc8 phosphorylation in vivo. In vitro kinase assays and genetic results indicate that Pho85 cyclins Pcl6 and Pcl7 comprise the predominant Glc8 kinase.
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PMID:Pho85 phosphorylates the Glc7 protein phosphatase regulator Glc8 in vivo. 1240 5

Protein kinases and phosphatases play antagonistic roles in regulating hippocampal long-term potentiation (LTP), with kinase inhibition and phosphatase activation both impairing LTP. The late phase of LTP (L-LTP) requires activation of cAMP-dependent protein kinase (PKA) for its full expression. One way in which PKA may critically modulate L-LTP is by relieving an inhibitory constraint imposed by protein phosphatases. Using mutant PKA mice [R(AB) transgenic mice] that have genetically reduced hippocampal PKA activity, we show that deficient L-LTP in area CA1 of mutant hippocampal slices is rescued by acute application of two inhibitors of protein phosphatase-1 and protein phosphatase-2A (PP1/2A) (okadaic acid and calyculin A). Furthermore, synaptic facilitation induced by forskolin, an adenylyl cyclase activator, was impaired in R(AB) transgenics and was also rescued by a PP1/2A inhibitor in mutant slices. Inhibition of PP1/2A did not affect early LTP (E-LTP) or basal synaptic transmission in mutant and wildtype slices. Our data show that genetic inhibition of PKA impairs L-LTP by reducing PKA-mediated suppression of PP1/2A.
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PMID:Genetic and pharmacological demonstration of a role for cyclic AMP-dependent protein kinase-mediated suppression of protein phosphatases in gating the expression of late LTP. 1245 50

Abnormally hyperphosphorylated tau polymers known as paired helical filaments constitute one of the major characteristic lesions that lead to the demise of neurons in Alzheimer's disease. Here, we demonstrate that the environmental toxin arsenite causes a significant increase in the phosphorylation of several amino acid residues (Thr-181, Ser-202, Thr-205, Thr-231, Ser-262, Ser-356, Ser-396, and Ser-404) in tau, which are also hyperphosphorylated under pathological conditions. Complementary phosphopeptide mapping revealed a dramatic increase in the (32)P-labeling of many peptides in tau following arsenite treatment. Although arsenite activates extracellular-signal regulated kinases-1/-2 and stress-activated protein kinases, these enzymes did not contribute to the arsenite-increased phosphorylation, nor did they appear to normally modify tau in vivo. Tau phosphorylation induced by arsenite did not involve glycogen synthase kinase-3 or protein phosphatase-1 or -2, but the activity responsible for tau hyperphosphorylation could be inhibited with the protein kinase inhibitor roscovitine. The effects of arsenite on the phosphorylation of some tau mutations (DeltaKappa280, V337M, and R406W) associated with frontal-temporal dementia with parkinsonism linked to chromosome 17 was analyzed. The unchallenged and arsenite-induced phosphorylation of some mutant proteins, especially R406W, was altered at several phosphorylation sites, indicating that these mutations can significantly affect the structure of tau in vivo. Although the major kinase(s) involved in aberrant tau phosphorylation remains elusive, these results indicate that environmental factors, such as arsenite, may be involved in the cascade leading to deregulation of tau function associated with neurodegeneration.
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PMID:The environmental toxin arsenite induces tau hyperphosphorylation. 1248 77

To develop our knowledge of specificity determinants for protein phosphatase-1, mutants of phosphorylase b have been converted to phosphorylase a and examined for their efficacy as substrates for protein phosphatase-1. Mutants focused on the N-terminal primary sequence surrounding the phosphoserine (R16A, R16E, and I13G) and at a site that interacts with the phosphoserine in phosphorylase a, (R69K and R69E). The success achieved studying protein kinase substrate specificity with peptide substrates has not extended to protein phosphatases. Protein phosphatases are believed to recognize higher order structure in substrates in addition to the primary sequence surrounding the phosphoserine or threonine. Peptide studies with protein phosphatase-1 have revealed a preference for basic residues N-terminal to the phosphoserine. Arginine 16 in phosphorylase a may be a positive determinant. In this work, protein phosphatase-1 preferred the positive charge on arginine 16. R16A exhibited a similar K(m) but reduced V(max), and R16E had an increased K(m) and a decreased V(max) when compared to phosphorylase. I13G had a similar K(m) but an increased V(max). The R69 mutants were also dephosphorylated preferentially over phosphorylase a. The K(m) for R69K was unchanged but had a higher V(max). R69E exhibited the most changes, with a 4-fold increase in K(m) and a 10-fold increase in V(max). These results suggest that proper presentation of the phosphoserine can greatly affect the rate of dephosphorylation.
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PMID:Mutants of phosphorylase a altered in recognition by protein phosphatase-1. 1262 67

Inhibitor-2 (I2) is a thermostable protein that specifically binds to the catalytic subunit of protein phosphatase-1 (PP1), resulting in the formation of the inactive holoenzyme, ATP-Mg-dependent phosphatase. Phosphorylation of I2 at Thr-72 by glycogen synthase kinase-3 (GSK-3) results in activation of the phosphatase, suggesting that kinase action triggers conformational change in the complex. In this paper, we characterize the effect of GSK-3 phosphorylation on the structure of free state I2[1-172] by nuclear magnetic resonance and circular dichroism spectroscopy, and show that phosphorylation has no significant effect on its conformation. We conclude that the conformational changes of ATP-Mg-dependent phosphatase induced by GSK-3 phosphorylation must depend on the interactions between PP1 and I2.
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PMID:Phosphorylation by glycogen synthase kinase of inhibitor-2 does not change its structure in free state. 1462 75

We have identified a new binding partner of the TGFbeta (transforming growth factor-beta)-activated protein kinase (TAK1), termed TAB3 (TAK1-binding protein-3), which shares 48% amino acid sequence identity with TAB2. Our results indicate that two distinct TAK1 complexes are present in cells. One comprises TAK1 complexed with TAB1 and TAB2, and the other TAK1 complexed with TAB1 and TAB3. Both complexes are activated in response to tumour necrosis factor-alpha or interleukin-1 in human epithelial KB cells or bacterial lipopolysaccharide in RAW264.7 macrophages, and are subject to feedback control by stress-activated protein kinase 2a (SAPK2a; also called p38alpha). The electrophoretic mobility of TAB2 and TAB3 decreases in response to these agonists or osmotic shock, and is reversed by treatment with protein phosphatase-1. The decrease in mobility of TAB3 is prevented if the cells are incubated with SB 203580 before stimulation, but treatment with SB 203580 produces forms of TAB2 with a mobility intermediate between that observed for TAB2 in unstimulated and stimulated cells. Similar results were obtained in embryonic fibroblasts from mice deficient in SAPK2a/p38alpha. Our results indicate that TAB3 is phosphorylated via the SAPK2a/p38alpha pathway, whereas TAB2 is phosphorylated at two or more sites by both an SAPK2a/p38alpha-dependent and an SB 203580-independent kinase. The SAPK2a/p38alpha-mediated phosphorylation of TAB2 and TAB3 may contribute to the SAPK2a/p38alpha-mediated feedback control of TAK1 activity that also involves the phosphorylation of TAB1. We also show that the agonist-induced activation of TAK1 complexes requires the phosphorylation of the TAK1 catalytic subunit at a serine/threonine residue(s).
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PMID:TAB3, a new binding partner of the protein kinase TAK1. 1467 75

Dopamine- and cAMP-regulated phosphoprotein, Mr 32 kDa (DARPP-32), was identified initially as a major target for dopamine and protein kinase A (PKA) in striatum. However, recent advances now indicate that regulation of the state of DARPP-32 phosphorylation provides a mechanism for integrating information arriving at dopaminoceptive neurons, in multiple brain regions, via a variety of neurotransmitters, neuromodulators, neuropeptides, and steroid hormones. Activation of PKA or PKG stimulates DARPP-32 phosphorylation at Thr34 and thereby converts DARPP-32 into a potent inhibitor of protein phosphatase-1 (PP-1). DARPP-32 is also phosphorylated at Thr75 by Cdk5 and this converts DARPP-32 into an inhibitor of PKA. Thus, DARPP-32 has the unique property of being a dual-function protein, acting either as an inhibitor of PP-1 or of PKA. The state of phosphorylation of DARPP-32 at Thr34 depends on the phosphorylation state of two serine residues, Ser102 and Ser137, which are phosphorylated by CK2 and CK1, respectively. By virtue of its ability to modulate the activity of PP-1 and PKA, DARPP-32 is critically involved in regulating electrophysiological, transcriptional, and behavioral responses to physiological and pharmacological stimuli, including antidepressants, neuroleptics, and drugs of abuse.
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PMID:DARPP-32: an integrator of neurotransmission. 1474 47

Deoxycytidine kinase (dCK) is a key enzyme in the deoxynucleoside salvage pathway and in the activation of numerous nucleoside analogues used in cancer and antiviral chemotherapy. Recent studies indicate that dCK activity might be regulated through reversible phosphorylation. Here, we report the effects of a large panel of protein kinase inhibitors on dCK activity in the B-leukemia cell line EHEB, both in basal conditions and in the presence of the nucleoside analogue 2-chloro-2'-deoxyadenosine (CdA) which induces activation of dCK. Except staurosporine and H-7 that significantly reduced the activation of dCK by CdA, no specific protein kinase inhibitor diminished basal dCK activity or its activation by CdA. In contrast, genistein, a general protein tyrosine kinase inhibitor, and AG-490, an inhibitor of JAK2 and JAK3, increased basal dCK activity more than two-fold. Two specific inhibitors of the MAPK/ERK pathway, PD-98059 and U-0126, also enhanced dCK activity. These data suggest that the JAK/MAPK pathway could be involved in the regulation of dCK. Moreover, we show that the activity of dCK, raised by CdA, can return to its initial level by treatment with protein phosphatase-2A (PP2A). Accordingly, dCK activity in intact cells increased upon incubation with okadaic acid (OA) at concentrations that should inhibit PP2A, but not protein phosphatase-1. Activation of dCK by protein kinase inhibitors and OA was also observed in CCRF-CEM cells and in chronic lymphocytic leukemia B-lymphocytes, suggesting a general mechanism of post-translational regulation of dCK, which could be exploited to enhance the activation of antileukemic nucleoside analogues.
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PMID:Activation of deoxycytidine kinase by protein kinase inhibitors and okadaic acid in leukemic cells. 1518 21

The dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) is abundantly expressed in the medium spiny neurons of the striatum. Phosphorylation catalysed by cAMP-dependent protein kinase (PKA) converts DARPP-32 into an inhibitor of protein phosphatase-1. In contrast, phosphorylation catalysed by cyclin dependent kinase-5 on Thr75 converts DARPP-32 into an inhibitor of PKA. Changes in the state of phosphorylation of DARPP-32 reinforce the behavioral effects produced by stimulation or inhibition of the cAMP pathway. Dopamine, via D(1) receptors, and adenosine, via A(2A) receptors, affect motor behavior by acting on medium spiny neurons, via G(olf) mediated stimulation of the cAMP signaling cascade. The involvement of DARPP-32 in dopamine and adenosine transmission and the possible role played by abnormal regulation of DARPP-32 phosphorylation in levodopa-induced dyskinesia are discussed.
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PMID:DARPP-32 and modulation of cAMP signaling: involvement in motor control and levodopa-induced dyskinesia. 1519 6


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