Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.69 (APC)
 16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In Dictyostelium, cAMP functions as an extracellular regulatory molecule that controls aggregation, expression of a number of classes of genes, and cellular differentiation by binding to cell-surface receptors that activate intracellular signal transduction pathways. To investigate possible roles for intracellular cAMP, we have overexpressed the wild-type mouse type-I regulatory subunit (RI) of cAMP-dependent protein C (PKA) in Dictyostelium cells, as well as mutant forms of the subunit that are altered in their ability to bind cAMP. We show that overexpression of a mutated RI, which lacks both cAMP-binding sites and presumably forms a complex with the endogenous Dictyostelium catalytic subunit that cannot be activated by cAMP, results in cells that do not aggregate or express sets of genes that are normally induced in the multicellular stages. Transformations that express the mutant subunit at low levels show no observable phenotype. We show that these cells can respond to pulses of cAMP and activate cAMP receptor/G protein-mediated processes, including the activation of adenylate and guanylate cyclases and the induction of a class of genes known to be regulated through the receptor-mediated pathways; however, the cells do show an altered pattern of expression of other genes normally active during the preaggregation/interphase and aggregation stages. Of interest is a substantial overexpression of the developmentally regulated PDE mRNA. Cell lines carrying constructs encoding the wild-type subunit or mutant subunits lacking one of the two binding sites show no visual phenotype. The results suggest that PKA-mediated functions, presumably controlled by increases in intracellular cAMP, are essential for Dictyostelium aggregation.
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PMID:A role for cAMP-dependent protein kinase A in early Dictyostelium development. 196 13

The amino acid sequence analysis of the human and porcine aminoacylases-1, the carboxypeptidase S precursor from Saccharomyces cerevisiae, the succinyl-diaminopimelate desuccinylase from Escherichia coli, Haemophilus influenzae and Corynebacterium glutamicum, the acetylornithine deacetylase from Escherichia coli and Dictyostelium discoideum and the carboxypeptidase G(2) precursor from Pseudomonas strain, using the Basic Local Alignment Search Tool (BLAST) and the Position-Specific Iterated BLAST (PSI-BLAST), allowed us to suggest that all these enzymes, which share common functional and biochemical features, belong to the same structural family. The three amino acid blocks which were found to be highly conserved, using the CLUSTAL W program, could be assigned to the catalytic active site, based on the general three-dimensional structure of the carboxypeptidase G(2) from the Pseudomonas strain precursor. Six additional proteins with the same signature have been retrieved after performing two successive PSI-BLAST iterations using the sequence of the conserved motif, namely Lactobacillus delbrueckii aminoacyl-histidine dipeptidase, Streptomyces griseus aminopeptidase, Saccharomyces cerevisiae aminopeptidase Y precursor, two Bacillus stearothermophilus N-carbamyl-L-amino acid amidohydrolases and Pseudomonas sp. hydantoin utilization protein C. The three conserved amino acid motifs corresponded to the following blocks: (i) [S, G, A]-H-x-D-x-V; (ii) G-x-x-D; and (iii) x-E-E. This new sequence signature is clearly different from that commonly reported in the literature for proteins belonging to the ArgE/DapE/CPG2/YscS family.
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PMID:Sequence analysis of the aminoacylase-1 family. A new proposed signature for metalloexopeptidases. 1125 May 42

A unique feature of colon cancer is that truncation mutations in the APC (adenomatous polyposis coli) gene are common to most tumours. The high penetrance of APC mutations, especially in gut epithelium, supports the idea that APC may be involved in a number of the processes that govern the normal maintenance of this tissue: differentiation, migration, proliferation and apoptosis. Indeed, APC is involved in the regulation of beta-catenin and it also is an important regulator of the cytoskeleton. Thus mutations in APC lead to the accumulation of beta-catenin, which causes changes in differentiation, and they also produce changes in cytoskeletal organization, which results in altered cell migration and disrupted mitotic spindles. The function of APC in cytoskeletal organization is related to its effect on microtubules and F-actin. Depleting APC from cultured cells leads to changes in cytoskeletal organization. In addition, N-terminal fragments of APC, like those commonly found in tumours, compromise cell migration in Dictyostelium and in early developing chicken embryos. Consistent with the idea that such dominant effects are normally balanced by interactions within the full-length molecule, protein interactions of N-terminal fragments expressed in tumour cells can be altered by binding to C-terminal regions of APC commonly lost in tumours. This review summarizes effects of APC on the cytoskeleton and discusses how these functions of APC may contribute to its role in cancer.
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PMID:Relationship between the role of the adenomatous polyposis coli protein in colon cancer and its contribution to cytoskeletal regulation. 1604 76

Switching between attractive and repulsive migration in cell movement in response to extracellular guidance cues has been found in various cell types and is an important cellular function for translocation during cellular and developmental processes. Here we show that the preferential direction of migration during electrotaxis in Dictyostelium cells can be reversed by genetically modulating both guanylyl cyclases (GCases) and the cyclic guanosine monophosphate (cGMP)-binding protein C (GbpC) in combination with the inhibition of phosphatidylinositol-3-OH kinases (PI3Ks). The PI3K-dependent pathway is involved in cathode-directed migration under a direct-current electric field. The catalytic domains of soluble GCase (sGC) and GbpC also mediate cathode-directed signaling via cGMP, whereas the N-terminal domain of sGC mediates anode-directed signaling in conjunction with both the inhibition of PI3Ks and cGMP production. These observations provide an identification of the genes required for directional switching in electrotaxis and suggest that a parallel processing of electric signals, in which multiple-signaling pathways act to bias cell movement toward the cathode or anode, is used to determine the direction of migration.
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PMID:Switching direction in electric-signal-induced cell migration by cyclic guanosine monophosphate and phosphatidylinositol signaling. 1934 84

Oscillation of chemical signals is a common biological phenomenon, but its regulation is poorly understood. At the aggregation stage of Dictyostelium discoideum development, the chemoattractant cAMP is synthesized and released at 6-min intervals, directing cell migration. Although the G protein-coupled cAMP receptor cAR1 and ERK2 are both implicated in regulating the oscillation, the signaling circuit remains unknown. Here we report that D. discoideum arrestins regulate the frequency of cAMP oscillation and may link cAR1 signaling to oscillatory ERK2 activity. Cells lacking arrestins (adcB(-)C(-)) display cAMP oscillations during the aggregation stage that are twice as frequent as for wild- type cells. The adcB(-)C(-) cells also have a shorter period of transient ERK2 activity and precociously reactivate ERK2 in response to cAMP stimulation. We show that arrestin domain-containing protein C (AdcC) associates with ERK2 and that activation of cAR1 promotes the transient membrane recruitment of AdcC and interaction with cAR1, indicating that arrestins function in cAR1-controlled periodic ERK2 activation and oscillatory cAMP signaling in the aggregation stage of D. discoideum development. In addition, ligand-induced cAR1 internalization is compromised in adcB(-)C(-) cells, suggesting that arrestins are involved in elimination of high-affinity cAR1 receptors from cell surface after the aggregation stage of multicellular development.
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PMID:Arrestins function in cAR1 GPCR-mediated signaling and cAR1 internalization in the development of Dictyostelium discoideum. 2514 5

In eukaryotic chemotaxis, parallel signaling pathways regulate the spatiotemporal pseudopod dynamics at the leading edge of a motile cell through the characteristic dynamics of an excitable system; however, differences in the excitability and the physiological roles of individual pathways remain to be elucidated. Here, we found that two different pathways, mediated by soluble guanylyl cyclase (sGC) and phosphoinositide 3-kinase (PI3K), caused similar all-or-none responses for sGC localization and phosphatidylinositol 3,4,5-trisphosphate production but with different refractory periods, by undertaking simultaneous observations of the excitable properties of the two pathways in Dictyostelium cells. Owing to the shorter refractory period, sGC signaling responded more frequently to chemoattractants, leading to pseudopod formation with higher frequency. sGC excitability was regulated negatively by its product cGMP and by cGMP-binding protein C (GbpC) through the suppression of F-actin polymerization, providing the underlying delayed negative-feedback mechanism for the cyclical pseudopod formation. These results suggest that parallel pathways respond to environmental cues on different timescales in order to mediate chemotactic motility in a manner based on their intrinsic excitability.
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PMID:Parallel signaling pathways regulate excitable dynamics differently to mediate pseudopod formation during eukaryotic chemotaxis. 3040 36