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)

Analysis of a developmental mutant in Dictyostelium discoideum which is unable to initiate morphogenesis has shown that a protein kinase of the MAP kinase/ERK family affects relay of the cAMP chemotactic signal and cell differentiation. Strains in which the locus encoding ERK2 is disrupted respond to a pulse of cAMP by synthesizing cGMP normally but show little synthesis of cAMP. Since mutant cells lacking ERK2 contain normal levels of both the cytosolic regulator of adenylyl cyclase (CRAC) and manganese-activatable adenylyl cyclase, it appears that this kinase is important for receptor-mediated activation of adenylyl cyclase.
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PMID:A MAP kinase necessary for receptor-mediated activation of adenylyl cyclase in Dictyostelium. 784 54

Inhibition of cAMP production and consequent inactivation of protein kinase A (PKA) by the putative morphogen ammonia has been suggested to block culmination and stalk cell differentiation in Dictyostelium. Since other weak bases mimic and weak acids act oppositely to ammonia, its effects were attributed to cytosolic or vesicular alkalinization; the latter resulting in impaired Ca2+ sequestration. We investigated whether weak bases and acids modulate the activity of the two Dictyostelium adenylylcyclases ACA and ACG in a manner consistent with their effects on development. It appeared that ammonia inhibits both ACG activity and ACA activation only transiently and does not significantly affect cAMP levels in slugs. Surprisingly, weak acids inhibit both ACA and ACG permanently, but do not affect secretion of cAMP as was suggested earlier. The effects of weak acids, which reduce cytosolic pH, are consistent with the pH dependence of ACA and ACG. In lysates, basal and GTP gamma S-stimulated ACA activity as well as ACG activity are optimal at pH 8 and are virtually absent below pH 7. ACG activity in cell lysates is completely insensitive to Ca2+, while GTP gamma S-stimulated ACA activity is maximally 50% reduced by supraphysiological Ca2+ concentrations. The observation that weak acids strongly inhibit ACA and ACG while promoting a PKA-dependent process such as stalk cell differentiation suggests that in Dictyostelium PKA can be activated in the absence of cAMP production.
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PMID:Regulation of Dictyostelium adenylylcyclases by morphogen-induced modulation of cytosolic pH or Ca2+ levels. 788 72

The activity of cAMP-dependent protein kinase (PKA) is required for proper development at several stages during the Dictyostelium life cycle. We present evidence that activation of PKA is rate-limiting for the differentiation of prespore cells to spores and that PKA activation may be the developmental trigger for sporulation. Strains that overexpress the gene encoding the catalytic subunit of PKA (PKAcat) or lack a functional regulatory subunit (rdeC strains) undergo rapid, heterochronic development. We show that overexpression of PKAcat in prespore cell is sufficient to directly induce expression of the spore maturation marker spiA and differentiation to spores, in a cell-autonomous manner. Moreover, overexpression of PKAcat in prespore cells can bypass a mutation that blocks an earlier developmental step to induce spiA expression. Our results suggest that the regulatory pathway in prespore cells between the activation of PKA and spiA induction/spore maturation is quite short and that PKAcat expression in prespore cells may mediate spore differentiation at the level of transcription. This induction of sporulation requires the prior activation of the prespore cell pathway. In addition, we show that beta-galactosidase activity expressed from a PKAcat promoter/lacZ reporter construct is highly enriched in the anterior prestalk A region during the tipped aggregate, slug, and early culminant stages and that this pattern switches abruptly to a prespore pattern at the time of spore maturation, supporting the proposed role of PKA in this process.
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PMID:Expression of cAMP-dependent protein kinase in prespore cells is sufficient to induce spore cell differentiation in Dictyostelium. 793 93

A few hours after the onset of starvation, amoebae of Dictyostelium discoideum start to form multicellular aggregates by chemotaxis to centers that emit periodic cyclic AMP signals. There are two major developmental decisions: first, the aggregates either construct fruiting bodies directly, in a process known as culmination, or they migrate for a period as "slugs." Second, the amoebae differentiate into either prestalk or prespore cells. These are at first randomly distributed within aggregates and then sort out from each other to form polarized structures with the prestalk cells at the apex, before eventually maturing into the stalk cells and spores of fruiting bodies. Developmental gene expression seems to be driven primarily by cyclic AMP signaling between cells, and this review summarizes what is known of the cyclic AMP-based signaling mechanism and of the signal transduction pathways leading from cell surface cyclic AMP receptors to gene expression. Current understanding of the factors controlling the two major developmental choices is emphasized. The weak base ammonia appears to play a key role in preventing culmination by inhibiting activation of cyclic AMP-dependent protein kinase, whereas the prestalk cell-inducing factor DIF-1 is central to the choice of cell differentiation pathway. The mode of action of DIF-1 and of ammonia in the developmental choices is discussed.
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PMID:Developmental decisions in Dictyostelium discoideum. 796 18

Dictyostelium discoideum cells contain cell surface cyclic AMP (cAMP) receptors that bind cAMP as a first messenger and intracellular cAMP receptors that bind cAMP as a second messenger. Prolonged incubation of Dictyostelium cells with cAMP induces a sequential process of phosphorylation, sequestration and down-regulation of the surface receptors. The role of intracellular cAMP in down-regulation of surface receptors was investigated. Down-regulation of receptors does not occur under conditions that specifically inhibit the formation of intracellular cAMP (the drug caffeine or mutant cells lacking adenylate cyclase) or conditions that inhibit the function of intracellular cAMP (mutants lacking protein kinase A activity). Cell-permeable non-hydrolysable cAMP derivatives were used to investigate further the requirement of intracellular cAMP for down-regulation. The Sp isomer of 6-thioethylpurineriboside 3',5'-phosphorothioate (6SEth-cPuMPS) does not bind to the surface receptor, enters the cell and has relative high affinity for protein kinase A. 6SEth-cPuMPS alone has no effect on down-regulation. However, together with an agonist of the surface receptor, the analogue induces down-regulation in caffeine-treated wild-type cells and in mutant cells lacking adenylate cyclase, but not in mutant cells lacking protein kinase A. These results indicate that intracellular cAMP formation and activation of protein kinase A are essential for down-regulation of the surface cAMP receptor.
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PMID:Intracellular adenosine 3',5'-phosphate formation is essential for down-regulation of surface adenosine 3',5'-phosphate receptors in Dictyostelium. 798 Apr 15

A comparison of the sequences of the mammalian and Dictyostelium catalytic subunits of cAMP-dependent protein kinase revealed extensive sequence similarities through the catalytic core and the carboxy terminal tail. The amino terminal sequences however differ dramatically. The large difference in size, 73 kDa for the Dictyostelium enzyme versus 40 kDa is due to an extension in the N-terminus. The mouse enzyme has at its amino-terminus a long amphipatic helix, the A-helix, that precedes the catalytic core, covering the surface of both lobes of the enzyme. Dictyostelium does in fact, have a similar motif but it is remote from the catalytic core, in the N-terminal extension. On the basis of molecular modeling, it is proposed that residues 77-98 correspond to a structural motif similar to the A-helix in mouse catalytic subunit. Sequences encoding similar putative motifs contiguous to the catalytic core can be recognized in many other protein kinases and is particularly prominent in all of the non-receptor tyrosine kinases. In the case of Src, this A-helix motif appears to serve as the linker between the conserved catalytic core and the SH2 domain. The interaction between the A-helix motif and the core is described, and the general occurrence of this structure within the protein kinase family is discussed.
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PMID:Protein kinases share a common structural motif outside the conserved catalytic domain. 798 16

Dictyostelium discoideum cells use cyclic AMP (cAMP) for chemotactic signaling as well as for differentiation. The precise regulation of the cytosolic Ca2+ concentration ([Ca2+]i) seems to play a key role for both processes. We performed single cell measurements of [Ca2+]i in amoebae that were starved in suspension for various times and scrape-loaded with the Ca2+ indicator fura-2. Stimulation of cells with cAMP at the concentration required to induce gene expression (> or = 100 microM) elicited a global transient increase in [Ca2+]i that depended on the presence of external Ca2+. Both vegetative and aggregation-competent cells displayed a rise in [Ca2+]i, with aggregation-competent cells responding more often than vegetative cells. Basal [Ca2+]i in the presence of Ca2+ was high in vegetative cells and declined during development; the cAMP-induced rise in [Ca2+]i was higher and lasted longer in vegetative cells than in aggregative cells. The addition of 2'-deoxy-cAMP, which binds to the cAMP receptor, induced an increase in [Ca2+]i, whereas the membrane-permeant analogue 8-bromo-cAMP that has a low affinity for the receptor but activates cAMP-dependent protein kinase had no effect. This indicates that the change in [Ca2+]i is mediated by the cell surface cAMP receptor. Since HC85 mutant cells, which lack the G alpha 2 subunit of the G-protein that couples the receptor to phospholipase C, also responded to stimulation with cAMP, the Ca2+ influx does not seem to be triggered by the phosphoinositide signaling cascade.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Challenge with high concentrations of cyclic AMP induces transient changes in the cytosolic free calcium concentration in Dictyostelium discoideum. 798 72

Dictyostelium slugs expressing a dominant inhibitor of the cAMP-dependent protein kinase (PKA) selectively in prestalk cells are insensitive to the environmental signals that normally induce culmination (Harwood et al., 1992a). When such slugs do, eventually, attempt to culminate they are unable to activate stalk-specific gene expression and they become arrested in their development. We show here that they are also about half the size of normal slugs and that they move at about half normal speed, even after their size difference has been taken into account. They are also less accurate in orienting their direction of movement towards the light. Thus, in addition to its role in cellular differentiation, PKA is required for several important aspects of slug behaviour.
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PMID:Inhibition of cAMP-dependent protein kinase in Dictyostelium prestalk cells impairs slug migration and phototaxis. 802 34

Analysis of the expression patterns of two genes encoding extracellular matrix proteins shows there to be an unexpectedly complex pattern of prestalk cell differentiation and movement during the morphogenesis of Dictyostelium. The organism employs both cell sorting and positional differentiation to generate a patterned structure but these two mechanisms are used at different times during development. During slug formation prestalk cells arise at scattered positions within the aggregate and then move to its apex to form the tip. In contrast, during culmination, stalk cell differentiation occurs in a positionally localized manner at the entrance to the stalk tube. Two interacting signalling pathways regulate the differentiation of prestalk and stalk cells. Prestalk cell differentiation is induced by DIF, a chlorinated hexaphenone, and a repression mechanism prevents DIF acting to induce premature stalk cell differentiation during slug migration. At culmination intracellular cAMP levels rise, the cAMP dependent protein kinase (PKA) is activated and the block to stalk cell differentiation is lifted. Activation of PKA is also necessary in order that prestalk cells move to the entrance of the stalk tube at culmination. Thus, in Dictyostelium, PKA plays a role both in the regulation of cellular differentiation and in morphogenetic cell movement.
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PMID:Interacting signalling pathways regulating prestalk cell differentiation and movement during the morphogenesis of Dictyostelium. 804 65

A serine/threonine protein kinase that binds phorbol esters and diacylglycerol (named protein kinase D, PKD) has been identified. PKD contains membrane localization signals and a cysteine-rich repeat sequence homologous to that seen in the regulatory domain of protein kinase C (PKC). A bacterially expressed N-terminal domain of PKD exhibited high-affinity phorbol ester binding activity (Kd = 35 nM). The diacylglycerol analog 1-oleoyl-2-acetylglycerol inhibited phorbol ester binding in a dose-dependent manner. The catalytic domain of PKD contains all characteristic sequence motifs of serine protein kinases but shows only a low degree of sequence similarity to PKCs. The highest identity is with the catalytic domain of myosin light-chain kinase from Dictyostelium (41%). The bacterially expressed catalytic domain of PKD efficiently phosphorylated the exogenous peptide substrate syntide 2 in serine but did not catalyze significant phosphorylation of a variety of other substrates used by PKCs and other major second messenger regulated kinases. PKD may be an unusual component in the transduction of diacylglycerol and phorbol ester signals.
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PMID:Molecular cloning and characterization of protein kinase D: a target for diacylglycerol and phorbol esters with a distinctive catalytic domain. 807 25


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