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PubMed2003

A Ral guanine exchange factor-Ral pathway is conserved in Drosophila melanogaster and sheds new light on the connectivity of the Ral, Ras, and Rap pathways.

Ras GTPases are central to many physiological and pathological signaling pathways and act via a combination of effectors. In mammals, at least three Ral exchange factors (RalGEFs) contain a Ras association domain and constitute a discrete subgroup of Ras effectors. Despite their ability to bind activated Rap as well as activated Ras, they seem to act downstream of Ras but not downstream of Rap. We have revisited the Ras/Rap-Ral connections in Drosophila melanogaster by using iterative two-hybrid screens with these three GTPases as primary baits and a subsequent genetic approach. We show that (i) the Ral-centered protein network appears to be extremely conserved in human and flies, (ii) in this network, RGL is a functional Drosophila orthologue of RalGEFs, and (iii) the RGL-Ral pathway functionally interacts with both the Ras and Rap pathways. Our data do not support the paradigmatic model where Ral is in the effector pathway of Ras. They reveal a signaling circuitry where Ral is functionally downstream of the Rap GTPase, at odds with the pathways described for mammalian cell lines. Thus, in vivo data show variations in the connectivity of pathways described for cell lines which might display only a subset of the biological possibilities.

Alleles↗

PubMed2002

Pharmacological interventions for recurrent abdominal pain (RAP) in childhood.

BACKGROUND: Between 4% and 25% of school age children complain of recurrent abdominal pain (RAP) of sufficient severity to interfere with daily activities. For the majority of such children no organic cause for their pain can be found on physical examination or investigation. Although most children are likely managed by reassurance and simple measures, a large range of interventions has been recommended. OBJECTIVES: To determine the effectiveness of medication for recurrent abdominal pain in school-age children. SEARCH STRATEGY: The Cochrane Library (CENTRAL), MEDLINE, EMBASE, CINAHL, ERIC, PsycLIT, LILACS and JICST were searched using a strategy combining (Recurrent OR synonyms) AND (Abdomen OR synonyms) AND (Pain OR synonyms). Where appropriate search filters were employed. In addition, researchers working in this area were asked to identify relevant studies. SELECTION CRITERIA: Any study in which the majority of participants were school age children fulfilling standard criteria for RAP, and who were allocated by random or quasi-random methods to any drug treatment compared with a placebo or no treatment. DATA COLLECTION AND ANALYSIS: References identified by the searches were screened against the inclusion criteria by two independent reviewers. MAIN RESULTS: Only one trial met the inclusion criteria. This cross-over trial in 14 children who met suggested criteria for "abdominal migraine" compared pizotifen and placebo, each given for one month with no washout period. Participants reported a mean of 8.21 (95% CI 2.93, 13.48) fewer days of pain while taking the active drug. They also reported that the mean difference on an "Index of Severity" was -16.21 (95% CI -26.51, -5.90) and on an "Index of Misery" was -56.07 (95% CI -94.07, -18.07). REVIEWER'S CONCLUSIONS: There is little evidence to suggest that recommended drugs are effective in the management of RAP. At present there seems little justification for the use of these drugs other than in clinical trials. There is an urgent need for trials of all suggested pharmacologic interventions in children with RAP.

Abdominal Pain↗

PubMed2006

A promoter element of the CD-RAP gene is required for repression of gene expression in non-cartilage tissues in vitro and in vivo.

The cartilage-derived retinoic acid-sensitive protein (CD-RAP) gene is expressed predominately in cartilage. Previous studies in transgenic mice have shown that the DNA promoter segment from -2,251 bp to -2,068 bp of the CD-RAP gene contains elements critical for gene expression. Subsequent studies revealed both positive and negative regulatory motifs in this 183 bp element. Here we show that this element demonstrates activation or repression of gene expression in vitro and in vivo based on cell type and content of transcription factors. The distribution of Sox (positive) and C/EBP (negative) transcription factors in cell lines and in mouse tissues is consistent with their positive and negative roles. In transgenic mice, when the 183-bp element was removed from a 3,345-bp cartilage-specific CD-RAP promoter, expression of the reporter gene became widespread, being observed in muscle, bone, lung, and liver in addition to cartilage. In vitro, mutation of the C/EBP site activated the inactive 3,345-bp CD-RAP gene promoter in myoblastic cells, suggesting that this site is responsible for (-2,079 bp) repression. These results indicate that the 183-bp element plays an important role in cartilage-specific gene expression by acting as a chondrocyte-regulatory module repressing transcription in non-chondrocytes and contributing to activation in chondrocytes. This is the first report of a functional DNA element necessary for repression in non-cartilage tissues in vivo.

Animals↗

PubMed2006

Differential capacity of anti-RAP and anti-megalin antibodies to produce progressive passive Heymann nephritis - implications for the pathogenesis of idiopathic human membranous glomerulonephritis.

Passive Heymann nephritis (PHN) induced with heterologous antisera has been described according to various criteria, which may or may not include induction of chronic disease and proteinuria. Characteristics of the glomerular immune deposits determined by the antigenic specificities of the antisera presumably account for differences in disease outcome. In this study, the clinical and immunohistological features in the model produced with monospecific antisera were compared against megalin or receptor associated protein (RAP), two proteins that have been implicated as target antigens in PHN. Rats injected with either anti-megalin or anti-RAP antiserum developed typical glomerular immune deposits of PHN when examined after 7 days. Although the deposits stained for complement, none of the animals had abnormal proteinuria in this time frame. Over a longer time course (7-16 weeks), immune deposits persisted and proteinuria increased to pathological levels in all animals injected with anti-megalin serum. By contrast, immune deposits had cleared from the kidneys of rats injected with anti-RAP antiserum when examined at 7-8 weeks post-injection and the proteinuria levels observed up to 13 weeks remained in the normal range. Additional doses of anti-RAP antiserum given 4 and 17 days after the first injection did not prolong the duration of glomerular immune deposits. These results demonstrate a clear divergence in pathogenic potential of antisera generated against the two renal antigens, which suggest differences in the immune deposits linked to a soluble antigen that is non-covalently bound to the podocyte membrane versus those linked to an integral membrane antigen. These observations could provide clues to the nature of the unknown glomerular autoantigen of idiopathic membranous glomerulonephritis in humans.

Animals↗

PubMed1994

Chromosomal localization of human genes for the LDL receptor family member glycoprotein 330 (LRP2) and its associated protein RAP (LRPAP1).

Glycoprotein 330 (gp330) is a member of a family of receptors with structural similarities to the low-density lipoprotein receptor. Gp330 is expressed by a number of specialized epithelia, including renal proximal tubules, where it can mediate endocytosis of ligands such as complexes of urokinase and the serpin, plasminogen activator inhibitor-1. Gp330 has also been shown to bind in vitro to lipoprotein lipase and apolipoprotein E-enriched beta VLDL, suggesting a role for this receptor in lipoprotein metabolism. The 39-kDa protein, referred to as receptor associated protein (RAP), binds to and copurifies with gp330 and antagonizes the ligand binding activity of gp330. In this paper, we report the use of homology-PCR cloning to isolate cDNAs encoding human gp330. Using gp330 cDNA and previously isolated human RAP cDNA probes, we performed fluorescence in situ hybridization to map the human chromosomal location of the genes for these proteins. The gene for gp330 was mapped at a single site on the long arm of human chromosome 2 on the border of bands 2q24-q31. The gene for RAP was mapped to the short arm of human chromosome 4 at position 4p16.3, which is in the region of the chromosomal deletion causing Wolf-Hirschhorn syndrome. The assignment of chromosomal map positions for gp330 and RAP genes will aid in the evaluation of their potential roles in human diseases such as Wolf-Hirschhorn syndrome and disorders of lipoprotein metabolism, such as atherosclerosis.

Base Sequence↗

PubMed2004

Decreased interactions of mutant muscle LIM protein (MLP) with N-RAP and alpha-actinin and their implication for hypertrophic cardiomyopathy.

Previous work has shown that mutations in muscle LIM protein (MLP) can cause hypertrophic cardiomyopathy (HCM). In order to gain an insight into the molecular basis of the disease phenotype, we analysed the binding characteristics of wild-type MLP and of the (C58G) mutant MLP that causes hypertrophic cardiomyopathy. We show that MLP can form a ternary complex with two of its previously documented myofibrillar ligand proteins, N-RAP and alpha-actinin, which indicates the presence of distinct, non-overlapping binding sites. Our data also show that, in comparison to wild-type MLP, the capacity of the mutated MLP protein to bind both N-RAP and alpha-actinin is significantly decreased. In addition, this single point mutation prevents zinc coordination and proper folding of the second zinc-finger in the first LIM domain, which consequently renders the protein less stable and more susceptible to proteolysis. The molecular basis for HCM-causing mutations in the MLP gene might therefore be an alteration in the equilibrium of interactions of the ternary complex MLP-N-RAP-alpha-actinin. This assumption is supported by the previous observation that in the pathological situation accompanied by MLP down regulation, cardiomyocytes try to compensate for the decreased stability of MLP protein by increasing the expression of its ligand N-RAP, which might finally result in the development of myocyte disarray that is characteristic of this disease.

Actinin↗

PubMed1996

RAP kinase, a new enzyme phosphorylating the acidic P proteins from Saccharomyces cerevisiae.

A new protein kinase, showing a high specificity for the ribosomal acidic P proteins (RAP kinase) has been purified and characterized from Saccharomyces cerevisiae extracts. Purification was carried out by four chromatographic steps, including DEAE-cellulose, phosphocellulose, heparin-Sepharose and P protein-Sepharose. The purified enzyme preparation contains only one polypeptide of around 55 kDa as determined by SDS gel electrophoresis and gradient centrifugation. RAP kinase is different from all previous well-characterized kinases and does not show cross-reaction with antibodies to the 71 kDa 60S ribosomal subunit-specific kinase PK60 previously reported. The enzyme uses ATP as a better phosphate donor and is less sensitive to heparin than casein kinase II but is moderately affected by salt. Among the different substrates tested, ribosomal acidic proteins are preferentially modified by RAP kinase, which phosphorylates only serine residues in the four P proteins as well as the related ribosomal protein P0. Casein is phosphorylated at a much lower level. All the data indicate that RAP kinase might be the enzyme responsible for the phosphorylation of the P proteins, and in this way may also participate in a possible translational regulatory mechanism.

Adenosine Triphosphate↗

PubMed2000

Role of rap in the biogenesis of lipoprotein receptors.

The LDL receptor gene family is composed of several endocytic receptors that share structural homology and function in cellular uptake of various ligands including lipoprotein particles. The complex structure of these lipoprotein receptors is highlighted by the presence of clusters of cysteine-rich ligand-binding repeats. An important feature that is shared by all these receptors is the inhibition of ligand interaction by a 39-kDa receptor-associated protein (RAP). Recent studies have shown that under physiological conditions RAP serves as a molecular chaperone to assist the folding of lipoprotein receptors and their safe passage through the secretory pathway. Several non-exclusive models have been proposed regarding the molecular mechanisms of RAP function as an antagonist for ligand interaction with the receptors and as a molecular chaperone within the early secretory pathway. Elucidation of these mechanisms may provide insights into how biogenesis of lipoprotein receptors can be regulated via the expression of RAP under physiological and pathological conditions.

Carrier Proteins↗

PubMed2002

Systematic source estimation of spikes by a combination of independent component analysis and RAP-MUSIC. I: Principles and simulation study.

OBJECTIVES: We propose a combination of independent component analysis (ICA) and recursively applied and projected multiple signal classification (RAP-MUSIC) as a new approach to dipole source estimation of epileptiform discharges. The method is minimally dependent on subjective decisions. METHODS: Ten electroencephalographic (EEG) data matrices were generated by computer, each matrix including real background activity from a normal subject and an array of added simulated spikes. Each spike was a summation of two transients originating from slightly different 'original dipole sources'. The unaveraged EEG matrices were decomposed by ICA, and source estimation was performed by applying RAP-MUSIC to the spatial information defined by the ICA components showing epileptiform activity in their waveform. For comparison, dipoles were also estimated from the same matrices using two existing methods: RAP-MUSIC based on eigen-decomposition of the covariance matrices of averaged spikes and common spatial pattern decomposition. RESULTS: In every simulated EEG data matrix, two dipoles close to the original sources were estimated by the present method. Their unaveraged activities were also similar to those of the original sources. The two existing methods gave less precise results than the proposed method. CONCLUSIONS: RAP-MUSIC based on ICA thus proved promising for source estimation of unaveraged epileptiform discharges.

Brain↗

PubMed2003

The fate of heavy metals (Zn, Cu, Pb, Cd and Cr) in an integrated wastewater treatment plant: two phase anaerobic reactor (RAP) - high rate algal pond (HRAP).

Removal of heavy metals (Zn, Cu, Pb, Cd and Cr) by an integrated wastewater treatment system, Two Phase Anaerobic Reactor (RAP) - High Rate Algal Pond (HRAP), was investigated. Results indicate a good reduction of these micro-pollutants by this system. Global elimination rates of treatment system are 80%, 87%, 38%, 60% and 63%, respectively for Zn, Cu, Pb, Cd and Cr. Primary treatment (RAP) was not involved in this reduction. Metal concentrations detected in RAP effluent are higher than those detected in raw wastewater. However, the essential metal removal was ensured by the HRAP and thetwo maturation ponds. Sedimentation of metals adsorbed on suspended matters is the principal factor that intervened in metal elimination by these ponds. Indeed, metal analysis of wastewater dissolved and particulate fractions showed that the majority of these cations was in particulate fraction, notably for Zn, Cu, Cd and Cr. Their distribution between these fractions evolved towards their solubilization, during the treatment. Otherwise, metal sediment analysis of different ponds showed that sludges accumulate important quantities of metals, especially in RAP sludges. Thereafter, Zn, Cu and Cd concentrations increased in HRAP sludges, but Pb and Cr contents decreased. However, in maturation pond sludges metal quantities are lower. On the other hand, metal contents in sludges are variable from upstream to downstream of each pond.

Adsorption↗

PubMed1997

Characterization of a family of bacterial response regulator aspartyl-phosphate (RAP) phosphatases.

We have characterized a novel family of response regulator aspartyl-phosphate (RAP) phosphatases found exclusively in gram-positive bacteria. The family consists of 15 members, 12 of which are from Bacillus subtilis. The N-terminal domains proved to be more highly conserved than the C-terminal domains, and a signature sequence for the family was derived from the former domains. Phylogenetic analyses revealed clustering patterns showing that all Bacillus proteins are closely related. Most of the Bacillus RAP phosphatase genes are followed by and are translationally coupled to small nonhomologous phosphatase regulator (phr) genes that encode exported peptides with regulatory functions. Most of the paralogous RAP phosphatases of B. subtilis may serve related functions in signal transduction systems. They appear to have arisen by relatively recent gene duplication events that occurred after the divergence of major groups within the gram-positive bacterial kingdom. We suggest that the N-terminal domains of the RAP phosphatases function in catalysis, whereas the C-terminal domains function in regulation.

Amino Acid Sequence↗

PubMed2004

Requirement of the Caenorhabditis elegans RapGEF pxf-1 and rap-1 for epithelial integrity.

The Rap-pathway has been implicated in various cellular processes but its exact physiological function remains poorly defined. Here we show that the Caenorhabditis elegans homologue of the mammalian guanine nucleotide exchange factors PDZ-GEFs, PXF-1, specifically activates Rap1 and Rap2. Green fluorescent protein (GFP) reporter constructs demonstrate that sites of pxf-1 expression include the hypodermis and gut. Particularly striking is the oscillating expression of pxf-1 in the pharynx during the four larval molts. Deletion of the catalytic domain from pxf-1 leads to hypodermal defects, resulting in lethality. The cuticle secreted by pxf-1 mutants is disorganized and can often not be shed during molting. At later stages, hypodermal degeneration is seen and animals that reach adulthood frequently die with a burst vulva phenotype. Importantly, disruption of rap-1 leads to a similar, but less severe phenotype, which is enhanced by the simultaneous removal of rap-2. In addition, the lethal phenotype of pxf-1 can be rescued by expression of an activated version of rap-1. Together these results demonstrate that the pxf-1/rap pathway in C. elegans is required for maintenance of epithelial integrity, in which it probably functions in polarized secretion.

Animals↗

PubMed1989

Phage genetic sites involved in lambda growth inhibition by the Escherichia coli rap mutant.

The rap mutation of Escherichia coli prevents the growth of bacteriophage lambda. We have isolated phage mutants that compensate for the host deficiency. The mutations, named bar, were genetically located to three different loci of the lambda genome: barI in the attP site, barII in the cIII ea10 region, and barIII within or very near the imm434 region. The level of lambda leftward transcription correlates with rap exclusion. Phage lambda mutants partially defective in the pL promoter or in pL-transcript antitermination showed a Bar- phenotype. Conversely, mutants constitutive for transcription from the pI or pL promoters were excluded more stringently by rap bacteria. We conclude that rap exclusion depends on the magnitude of transcription through the wild type bar loci in the phage genome.

Bacteriophage lambda↗

PubMed2003

A plasmid-borne Rap-Phr system of Bacillus subtilis can mediate cell-density controlled production of extracellular proteases.

Bacillus subtilis uses two-component signal transduction systems to sense intra- and extracellular stimuli to adapt to fluctuating environmental situations. Regulator aspartate phosphatases (Raps) have important roles in these processes, as they can dephosphorylate certain response-regulators, and are themselves subject to cell-density-controlled inhibition by secreted Phr (phosphate regulator) peptides. Eleven chromosomal genes encode this family of phosphatases, but in addition, certain strains contain endogenous plasmids with genes for homologous Rap-Phr systems. Plasmid pTA1060 encodes Rap60 and its antagonistic signalling molecule Phr60. Strikingly, expression of Rap60 in B. subtilis 168 strongly repressed the production of proteolytic enzymes. In fact, the transcription of the aprE gene, encoding a major extracellular protease, was shown to be decreased upon Rap60 expression, whereas this effect could be antagonized by the extracellular addition of synthetic Phr60 pentapeptide. Finally, transcription studies suggest that Rap60 dephosphorylates a component of the phosphorelay and is coupled to aprE transcription by the transition-state regulator AbrB. In conclusion, these data show that endogenous plasmids contain functional Rap-Phr systems and for the first time, that Rap-Phr systems can mediate cell-density controlled production of secreted proteases. This quorum-sensing mechanism might enable B. subtilis to suppress protease production under conditions of low cell densities when nutrients are still available in sufficient amounts.

Bacillus subtilis↗

PubMed2006

Efficient localization of synchronous EEG source activities using a modified RAP-MUSIC algorithm.

Synchronization across different brain regions is suggested to be a possible mechanism for functional integration. Noninvasive analysis of the synchronization among cortical areas is possible if the electrical sources can be estimated by solving the electroencephalography inverse problem. Among various inverse algorithms, spatio-temporal dipole fitting methods such as RAP-MUSIC and R-MUSIC have demonstrated superior ability in the localization of a restricted number of independent sources, and also have the ability to reliably reproduce temporal waveforms. However, these algorithms experience difficulty in reconstructing multiple correlated sources. Accurate reconstruction of correlated brain activities is critical in synchronization analysis. In this study, we modified the well-known inverse algorithm RAP-MUSIC to a multistage process which analyzes the correlation of candidate sources and searches for independent topographies (ITs) among precorrelated groups. Comparative studies were carried out on both simulated data and clinical seizure data. The results demonstrated superior performance with the modified algorithm compared to the original RAP-MUSIC in recovering synchronous sources and localizing the epileptiform activity. The modified RAP-MUSIC algorithm, thus, has potential in neurological applications involving significant synchronous brain activities.

Algorithms↗

PubMed1999

MDS+ items not contained in the pressure ulcer RAP associated with pressure ulcer prevalence in newly institutionalized elderly.

All federally funded facilities are required to use the Minimum Data Set Plus (MDS+) for functional assessment of their residents. Within the MDS+ there are 18 specific conditions addressed through Resident Assessment Protocols (RAPs). The purpose of this study was to determine if MDS+ items not included in the pressure ulcer RAP correlated with pressure ulcer prevalence in newly institutionalized elderly. Additionally, this study examined whether the addition of nutritional status information to the correlated items increased association with pressure ulcer prevalence. Data were collected through a retrospective chart review of 990 residents over age 65 at eight nursing homes. Pressure ulcer prevalence was 33.2%. Nineteen of 59 non-RAP MDS+ items were correlated with pressure ulcer prevalence. Logistic regression determined that 10 MDS+ items predicted pressure ulcer prevalence in 28.88% of the subjects. Including serum albumin in the logistic model increased the predictability for pressure ulcer prevalence to 36.3%. Results of this study demonstrate the strong association between nutrition and pressure ulcer prevalence and the need to revise the pressure ulcer RAP.

Aged↗

PubMed2006

The Rap GTPases mediate CXCL13- and sphingosine1-phosphate-induced chemotaxis, adhesion, and Pyk2 tyrosine phosphorylation in B lymphocytes.

The localization of B cells to lymphoid organs where they can become activated and differentiate into antibody-secreting plasma cells is controlled by multiple chemoattractants that promote cell migration and integrin-mediated adhesion. CXCL13 and sphingosine 1-phosphate (S1P) are two important chemoattractants that control the trafficking of B cells. CXCL13 directs B lymphocytes to lymphoid follicles where they receive survival signals and, if activated, undergo a germinal center response. In contrast, S1P allows B cells and plasma cells to exit lymphoid organs and re-enter the circulation. The Rap1 GTPase is a key regulator of cell adhesion and cell migration in a number of systems. We now show that Rap activation is required for CXCL13 and S1P to induce B cell migration as well as adhesion to ICAM-1 and VCAM-1. We also show that Pyk2, a tyrosine kinase involved in cytoskeleton rearrangements and B cell migration, is a downstream target of both CXCL13 and S1P signaling and that Rap activation is important for CXCL13 and S1P to stimulate tyrosine phosphorylation of Pyk2, a modification that increases Pyk2 kinase activity. This suggests that the ability of CXCL13 and S1P to direct the trafficking and localization of B cells in vivo may be dependent on Rap activation.

Animals↗

PubMed1989

Expression of the ras-related rap genes in human tumors.

The expression of the recently described rap genes, closely related in the effector region to the ras proto-oncogenes, was examined by Northern blot analysis in 41 primary human tumors. The structural and in vitro biological properties of the rap gene products suggest their possible antagonistic action in the same effector pathway as the ras proteins. In order to determine whether a deregulation in the rap transcription levels could be involved per se in the multistep carcinogenic process, we chose to analyze tumors for which the ras mutation rate was previously reported to be extremely rare or unknown, i.e., non-Hodgkin's lymphomas, certain types of carcinoma, sarcomas, germinal neoplasms of the testes and various tumors of the nervous system. A severe decrease in the expression of the rap1A gene was shown in the fibrosarcomas and the adenocarcinoma of the salivary gland studied, as compared to their normal counterparts, whereas no rap2 expression was found in the polyadenylated RNA of sarcoma samples.

Blotting, Northern↗