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)

A substrate for PKBalpha (protein kinase Balpha) was detected in liver extracts, and was purified and identified as CRHSP24 (calcium-regulated heat-stable protein of apparent molecular mass 24 kDa). PKBalpha, as well as SGK1 (serum- and glucocorticoid-induced protein kinase 1) and RSK (p90 ribosomal S6 kinase), phosphorylated CRHSP24 stoichiometrically at Ser52 in vitro and its brain-specific isoform PIPPin at the equivalent residue (Ser58). CRHSP24 became phosphorylated at Ser52 when HEK-293 (human embryonic kidney) cells were stimulated with IGF-1 (insulin-like growth factor-1) and this was prevented by inhibitors of PI3K (phosphoinositide 3-kinase), but not by rapamycin [an inhibitor of mTOR (mammalian target of rapamycin)] or PD 184352, an inhibitor of the classical MAPK (mitogen-activated protein kinase) cascade and hence the activation of RSK. IGF-1 induced a similar phosphorylation of CRHSP24 in ES (embryonic stem) cells from wild-type mice or mice that express the PDK1 (3-phosphoinositide-dependent kinase 1) mutant (PDK1[L155E]) that activates PKBalpha normally, but cannot activate SGK. CRHSP24 also became phosphorylated at Ser52 in response to EGF (epidermal growth factor) and this was prevented by blocking activation of both the classical MAPK cascade and the activation of PKBalpha, but not if just one of these pathways was inhibited. DYRK2 (dual-specificity tyrosine-phosphorylated and -regulated protein kinase 2) phosphorylated CRHSP24 at Ser30, Ser32 and Ser41 in vitro, and Ser41 was identified as a site phosphorylated in cells. These and other results demonstrate that CRHSP24 is phosphorylated at Ser52 by PKBalpha in response to IGF-1, at Ser52 by PKBalpha and RSK in response to EGF, and at Ser41 in the absence of IGF-1/EGF by a DYRK isoform or another proline-directed protein kinase(s).
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PMID:Identification of calcium-regulated heat-stable protein of 24 kDa (CRHSP24) as a physiological substrate for PKB and RSK using KESTREL. 1591 Feb 84

Serum- and glucocorticoid-induced protein kinase (SGK) is a serine/threonine-specific protein kinase that is transcriptionally regulated by serum, glucocorticoids, and mineral corticoids. Here, we report that fasting or obesity with hyperphagia increased hypothalamic SGK-1 gene expression. Hypothalamic SGK-1 mRNA levels were proportional to daily food intake and body weights in C57BL6J mice, KK mice, and KKA(y) mice matched for age. Plasma des-acyl ghrelin, but not active ghrelin, levels were inversely proportional to daily food intake and body weights among these animals. The increases in hypothalamic SGK-1 gene expression in these animals were not accompanied by increases in plasma corticosterone levels. Under conditions of increased energy usage such as fasting, hypothalamic SGK-1 gene expression and plasma des-acyl ghrelin levels were positively correlated while during conditions of increased energy storage, they were negatively correlated. These results suggest that hypothalamic SGK-1 gene is a novel candidate gene involving in energy homeostasis in mice.
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PMID:Induction of hypothalamic serum- and glucocorticoid-induced protein kinase-1 gene expression and its relation to plasma des-acyl ghrelin in energy homeostasis in mice. 1663 May 41

Abnormally high constitutive activity of protein kinase CK2, levels of which are elevated in a variety of tumours, is suspected to underlie its pathogenic potential. The most widely employed CK2 inhibitor is 4,5,6,7-tetrabromobenzotriazole (TBB), which exhibits a comparable efficacy toward another kinase, DYRK1 a. Here we describe the development of a new class of CK2 inhibitors, conceptually derived from TBB, which have lost their potency toward DYRK1 a. In particular, tetrabromocinnamic acid (TBCA) inhibits CK2 five times more efficiently than TBB (IC50 values 0.11 and 0.56 microM, respectively), without having any comparable effect on DYRK1 a (IC50 24.5 microM) or on a panel of 28 protein kinases. The usefulness of TBCA for cellular studies has been validated by showing that it reduces the viability of Jurkat cells more efficiently than TBB through enhancement of apoptosis. Collectively taken, the reported data support the view that suitably derivatized tetrabromobenzene molecules may provide powerful reagents for dissecting the cellular functions of CK2 and counteracting its pathogenic potentials.
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PMID:Tetrabromocinnamic acid (TBCA) and related compounds represent a new class of specific protein kinase CK2 inhibitors. 1713 43

Intrinsic spatial cues ensure the proper placement of the cell division plane. In the fission yeast Schizosaccharomyces pombe, the position of the nucleus helps to direct the medial positioning of contractile-ring assembly and subsequent cell division . An important factor in this process is mid1p (anillin-like protein), which is a peripheral-membrane protein that forms a broad cortical band of dots overlying the nucleus in interphase and recruits myosin in early mitosis . How mid1p localizes to this cortical band and tracks the nucleus is not clear, especially because its localization is independent of the cytoskeleton . Here, we used a combination of experimental and computational approaches to test mid1p localization mechanisms. We provide evidence that pom1p, a DYRK-family protein kinase that forms a concentration gradient emanating from the nongrowing cell end, inhibits mid1p. In pom1 mutants, mid1p is distributed over half of the cell, covering the nongrowing cell end. This abnormal distribution is established in a dynamic manner in interphase and leads to the formation of misplaced or multiple contractile rings. Our computational and experimental results support a model in which both positive cues from the medial nucleus and negative cues from the cell tips specify the position of the division plane.
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PMID:The cell-end factor pom1p inhibits mid1p in specification of the cell division plane in fission yeast. 1727 8

The dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) gene is localized in human chromosome 21, and its overexpression has been associated with the learning and memory deficits of Down syndrome. DYRK1A contains a Y319XY321 motif shared by all members of the DYRK protein kinase family. Residue Y321 in the motif is phosphorylated in DYRK1A prepared from Escherichia coli and from eukaryotic cells. It has been proposed that the YXY motif is an equivalent of the TXY motif, the activation loop, of mitogen-activated protein kinase and that phosphorylation at the motif is required for DYRK activity. In this study, the role of tyrosine phosphorylation in the activity of DYRK1A was investigated in detail. Wild-type DYRK1A with a reduced level of phosphotyrosine (pY) was prepared by treating E. coli-produced DYRK1A with two different protein tyrosine phosphatases. The resulting pY-depleted DYRK1A could not regain pY during autophosphorylation but was as active as the untreated control. These findings were further supported by the observation that DYRK1A retained significant enzymatic activity when both tyrosine residues in the YXY motif were replaced with either histidine or glutamine. Together, we conclude that tyrosine phosphorylation and tyrosine residues in the YXY motif are not directly involved in DYRK1A enzymatic activity in vitro.
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PMID:Dual-specificity tyrosine phosphorylation-regulated kinase 1A does not require tyrosine phosphorylation for activity in vitro. 1753 41

The identification of phosphorylation state-dependent interacting proteins provides clues as to the function of the phosphorylation. Techniques such as yeast two hybrid and co-immunoprecipitation do not employ a single species of fully phosphorylated proteins. This is a particular problem for substrates of glycogen synthase kinase-3 (GSK3), where multiple Ser/Thr residues can be targeted, almost always subsequent to a priming phosphorylation by an alternative kinase. We previously identified the brain enriched collapsin response mediator proteins (CRMP2 and CRMP4) as physiological substrates of GSK3. Cdk5 phosphorylates CRMP2 at Ser522, priming for subsequent phosphorylation at three residues by GSK3 in vitro and in vivo. It is clear that phosphorylation of CRMP2 influences axonal growth; however, the molecular processes underlying this action are not fully established. In addition, the role of phosphorylation in other actions of CRMPs has not been elucidated. We developed a novel procedure to isolate CRMP2 and CRMP4 fully phosphorylated at four sites, namely, Ser522 (by CDK5), Ser518, Thr514, and Thr509 (by GSK3). These phosphoproteins were then used to identify binding partners in rat brain lysates in direct comparison with the non-phosphorylated isoforms. We validated the approach by confirming that a previously reported interaction with tubulin-beta is regulated by phosphorylation. We also show that CRMPs (CRMP1, CRMP2, and CRMP4) form heteromers and found that these complexes may also be regulated by phosphorylation. We identified DYRK and Pin1 as novel CRMP4 binding proteins with DYRK interacting preferentially with dephospho-CRMP4 and Pin1 with phospho-CRMP4. Finally, we used this approach to identify the mitochondrial protein ANT as a novel CRMP2 and CRMP4 binding protein. We believe that this approach could be applied generally to the study of phosphorylation-dependent interactions.
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PMID:Novel procedure to investigate the effect of phosphorylation on protein complex formation in vitro and in cells. 1822 Apr 21

It is widely accepted that the neurological alterations in Down syndrome (DS) are principally due to modifications in developmental processes. Accordingly, a large part of the research on DS in recent years has focused on chromosome 21 genes that influence brain development. MNB/DYRK1A is one of the genes on human chromosome 21 that has raised most interest, due to its relationship with the brain functions that are altered in DS. Although a number of interesting experimental mouse models for DS are being developed, we still know little about the expression of Mnb/Dyrk1A during mouse brain development. Here, we report that Mnb/Dyrk1A displays a rather dynamic spatio-temporal expression pattern during mouse central nervous system development. Our data indicate that Mnb/Dyrk1A is specifically expressed in four sequential developmental phases: transient expression in preneurogenic progenitors, cell cycle-regulated expression in neurogenic progenitors, transient expression in recently born neurones, and persistent expression in late differentiating neurones. Our results also suggest that the subcellular localization of MNB/DYRK1A, including its translocation to the nucleus, is finely regulated. Thus, the MNB/DYRK1A protein kinase could be a key element in the molecular machinery that couples sequential events in neuronal development. This rich repertoire of potential functions in the developing central nervous system is suitable to be linked to the neurological alterations in DS through the use of mouse experimental models.
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PMID:The spatio-temporal and subcellular expression of the candidate Down syndrome gene Mnb/Dyrk1A in the developing mouse brain suggests distinct sequential roles in neuronal development. 1836 31

DYRK1A is a dual-specificity protein kinase that autophosphorylates a conserved tyrosine residue in the activation loop but phosphorylates exogenous substrates only at serine or threonine residues. Tyrosine autophosphorylation of DYRKs is a one-off event that takes place during translation and induces the activation of the kinase. Here we characterize the beta-carboline alkaloid harmine as a potent and specific inhibitor of DYRK1A both in vitro and in cultured cells. Comparative in vitro assays of four kinases of the DYRK family showed that harmine inhibited substrate phosphorylation by DYRK1A more potently than it inhibited substrate phosphorylation by the closely related kinase DYRK1B [half maximal inhibitory concentrations (IC(50)) of 33 nm versus 166 nm, respectively] and by the more distant members of the family, DYRK2 and DYRK4 (1.9 microm and 80 microm, respectively). Much higher concentrations of harmine were required to suppress tyrosine autophosphorylation of the translational intermediate of DYRK1A in a bacterial in vitro translation system (IC(50) = 1.9 microm). Importantly, harmine inhibited the phosphorylation of a specific substrate by DYRK1A in cultured cells with a potency similar to that observed in vitro (IC(50) = 48 nm), without negative effects on the viability of the cells. Overexpression of the DYRK1A gene on chromosome 21 has been implicated in the altered neuronal development observed in Down syndrome. Here, we show that harmine interferes with neuritogenesis in cultured hippocampal neurons. In summary, our data show that harmine inhibits DYRK1A substrate phosphorylation more potently than it inhibits tyrosine autophosphorylation, and provide evidence for a role of DYRK1A in the regulation of neurite formation.
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PMID:Harmine specifically inhibits protein kinase DYRK1A and interferes with neurite formation. 1979 73

Rho GTPase-activating proteins (GAPs) are responsible for the inactivation of Rho GTPases, which are involved in the regulation of critical biological responses in eukaryotic cells, ranging from cell cycle control to cellular morphogenesis. The genome of fission yeast Schizosaccharomyces pombe contains six genes coding for putative Rho GTPases, whereas nine genes code for predicted Rho GAPs (Rga1 to Rga9). One of them, Rga4, has been recently described as a Cdc42 GAP, involved in the control of cell diameter and symmetry in fission yeast. In this work we show that Rga4 is also a Rho2 GAP that negatively modulates the activity of the cell integrity pathway and its main effector, MAPK Pmk1. The DYRK-type protein kinase Pom1, which regulates both the localization and phosphorylation state of Rga4, is also a negative regulator of the Pmk1 pathway, but this control is not dependent upon the Rga4 role as a Rho2-GAP. Hence, two subsets of Rga4 negatively regulate Cdc42 and Rho2 functions in a specific and unrelated way. Finally, we show that Rga7, another Rho2 GAP, down-regulates the Pmk1 pathway in addition to Rga4. These results reinforce the notion of the existence of complex mechanisms determining the selectivity of Rho GAPs toward Rho GTPases and their functions.
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PMID:Rga4 modulates the activity of the fission yeast cell integrity MAPK pathway by acting as a Rho2 GTPase-activating protein. 2016 82

Chemical gradients can generate pattern formation in biological systems. In the fission yeast Schizosaccharomyces pombe, a cortical gradient of pom1p (a DYRK-type protein kinase) functions to position sites of cytokinesis and cell polarity and to control cell length. Here, using quantitative imaging, fluorescence correlation spectroscopy, and mathematical modeling, we study how its gradient distribution is formed. Pom1p gradients exhibit large cell-to-cell variability, as well as dynamic fluctuations in each individual gradient. Our data lead to a two-state model for gradient formation in which pom1p molecules associate with the plasma membrane at cell tips and then diffuse on the membrane while aggregating into and fragmenting from clusters, before disassociating from the membrane. In contrast to a classical one-component gradient, this two-state gradient buffers against cell-to-cell variations in protein concentration. This buffering mechanism, together with time averaging to reduce intrinsic noise, allows the pom1p gradient to specify positional information in a robust manner.
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PMID:Noise reduction in the intracellular pom1p gradient by a dynamic clustering mechanism. 2237 Nov 97


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