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PubMed1998

A Rap guanine nucleotide exchange factor enriched highly in the basal ganglia.

Ras proteins, key regulators of growth, differentiation, and malignant transformation, recently have been implicated in synaptic function and region-specific learning and memory functions in the brain. Rap proteins, members of the Ras small G protein superfamily, can inhibit Ras signaling through the Ras/Raf-1/mitogen-activated protein (MAP) kinase pathway or, through B-Raf, can activate MAP kinase. Rap and Ras proteins both can be activated through guanine nucleotide exchange factors (GEFs). Many Ras GEFs, but to date only one Rap GEF, have been identified. We now report the cloning of a brain-enriched gene, CalDAG-GEFI, which has substrate specificity for Rap1A, dual binding domains for calcium (Ca2+) and diacylglycerol (DAG), and enriched expression in brain basal ganglia pathways and their axon-terminal regions. Expression of CalDAG-GEFI activates Rap1A and inhibits Ras-dependent activation of the Erk/MAP kinase cascade in 293T cells. Ca2+ ionophore and phorbol ester strongly and additively enhance this Rap1A activation. By contrast, CalDAG-GEFII, a second CalDAG-GEF family member that we cloned and found identical to RasGRP [Ebinu, J. O., Bottorff, D. A., Chan, E. Y. W., Stang, S. L., Dunn, R. J. & Stone, J. C. (1998) Science 280, 1082-1088], exhibits a different brain expression pattern and fails to activate Rap1A, but activates H-Ras, R-Ras, and the Erk/MAP kinase cascade under Ca2+ and DAG modulation. We propose that CalDAG-GEF proteins have a critical neuronal function in determining the relative activation of Ras and Rap1 signaling induced by Ca2+ and DAG mobilization. The expression of CalDAG-GEFI and CalDAG-GEFII in hematopoietic organs suggests that such control may have broad significance in Ras/Rap regulation of normal and malignant states.

Amino Acid Sequence↗

PubMed2006

Rap-GEF/Rap signaling restricts the formation of supernumerary spermathecae in Drosophila melanogaster.

Sperm storage in the female is a key factor for reproductive success in a variety of organisms, including Drosophila melanogaster. The spermathecae (SP) are the Drosophila organs for long-term storage. While wild-type female flies have two SP, occasionally, three or four SP have been observed in mutant flies. However, the molecular mechanism of SP formation is unknown. Here we show that loss of function of a Drosophila Rap-GEF (GEF26) result in an occurrence of the supernumerary SP; females have three SP (varies from 11 to 62% in different allele combinations) instead of the normal two SP. In addition, the Gef26 mutant flies also have ectopic wing veins and extra mechanosensory organs. The supernumerary SP phenotype of the Gef26 mutation can be enhanced by the Drosophila Rap mutations and rescued by overexpressing the cell adhesion molecule DE-cadherin. These data suggest that the Rap-GEF/Rap signaling controls the formation of supernumerary spermathecae through modulating cell adhesion in Drosophila.

Animals↗

PubMed2002

The Rap GTPases regulate B cell migration toward the chemokine stromal cell-derived factor-1 (CXCL12): potential role for Rap2 in promoting B cell migration.

Stromal cell-derived factor-1 (SDF-1) is a potent chemoattractant for B cells and B cell progenitors. Although the binding of SDF-1 to its receptor, CXCR4, activates multiple signaling pathways, the mechanism by which SDF-1 regulates cell migration is not completely understood. In this report we show that activation of the Rap GTPases is important for B cells to migrate toward SDF-1. We found that treating B cells with SDF-1 resulted in the rapid activation of both Rap1 and Rap2. Moreover, blocking the activation of Rap1 and Rap2 via the expression of a Rap-specific GTPase-activating protein significantly reduced the ability of B cells to migrate toward SDF-1. Conversely, expressing a constitutively active form of Rap2 increased SDF-1-induced B cell migration. Thus, the Rap GTPases control cellular processes that are important for B cells to migrate toward SDF-1.

Animals↗

PubMed1990

Amino acid 61 is a determinant of sensitivity of rap proteins to the ras GTPase activating protein.

The GTPase activating protein (ras-GAP) has been shown to interact with p21ras at a domain defined by amino acids 32-40. The sequences of the rap family of ras related proteins (including a suppressor of ras transformation Krev-1/rap1A) are identical to ras in this region. Incubation of rap1A protein with ras-GAP does not accelerate the rate of GTP hydrolysis by p21rap1A. Rap proteins have threonine at amino acid 61, whereas ras proteins have glutamine at this site and mutation to threonine reduces the intrinsic GTPase of p21ras. We have, therefore, mutated thr61 of p21rap1A to glutamine and shown that ras-GAP is now able to accelerate the rate of hydrolysis of GTP. This demonstrates that ras-GAP can interact with rap and that the sensitivity to ras-GAP is determined in part by the amino acid at codon 61.

Amino Acid Sequence↗

PubMed1999

[Analysis of gene expression patterns in rheumatoid synovial fibroblasts using RAP-PCR for differential display].

OBJECTIVE: Destruction of articular cartilage and bone by invading synovial fibroblasts is a typical histopathologic feature in rheumatoid arthritis (RA). However, little is known about specific up- or downregulation of genes leading to this aggressive phenotype. Thus, our aim was to identify genes, which are differentially expressed in RA synovial fibroblasts as compared to synovial fibroblasts derived from patients with osteoarthritis (OA) using RAP-PCR for differential display. METHODS: After extraction of total RNA, the first step of RAP-PCR was performed using various different arbitrary 10-12-base primers for first-strand cDNA synthesis. Second-strand synthesis was achieved by cycling at low stringency conditions for 35 cycles using different arbitrary 10-base primers, followed by electrophoretic separation and sequence analysis of the amplified fingerprint products. RESULTS: On average, approximately 70 different RNAs were obtained per primer, of which most were expressed both by RA and OA synovial fibroblasts. Using 26 different primer combinations, in total 12 cDNAs were differentially expressed between RA and OA synovial fibroblasts. In the RA group strong amplification of distinct PCR products suitable for sequencing could be observed. Sequence analysis identified these PCR products as highly homologous to various genes involved in regulation of cell cycle and metabolism. CONCLUSION: The data indicate that RAP-PCR is a suitable method to identify differentially expressed genes in rheumatoid synovial fibroblasts potentially involved in the specific pathophysiology of RA.

Arthritis, Rheumatoid↗

PubMed1989

RAP-1 factor is necessary for DNA loop formation in vitro at the silent mating type locus HML.

DNA fragments containing the silencers that flank the mating type genes at HML alpha are shown to bind specifically to the nuclear scaffold of yeast. The scaffold proteins are solubilized with urea and then renatured to form a soluble extract which allows reconstitution of sequence-specific DNA loops. At the silent mating type locus HML alpha, loops are formed by either silencer-silencer (E-I) interaction or silencer-promoter interactions (E-P and I-P). The nuclear protein RAP-1 fractionates efficiently with the nuclear scaffold, and binds to the E, I, and promoter regions. Affinity purification of RAP-1 and oligonucleotide competition show that RAP-1 is necessary for reconstitution of loops in vitro. These results are consistent with a model in which silencers define a chromatin loop within which occur modifications that maintain the promoter in an inactive state.

Chromosome Mapping↗

PubMed2005

RAP, an integrated program for monitoring bioluminescence and analyzing circadian rhythms in real time.

To process the large number of circadian rhythmic bioluminescence data that we generated with specially developed, high-throughput monitoring apparatuses, we developed an integrated rhythm-analyzing program (RAP) with a user-friendly graphical interface. RAP does all of the following in real time: (i) displays the bioluminescence time course, (ii) records time-series data, (iii) analyzes the data, (iv) displays the analyzed results, (v) statistically evaluates the analyzed results, and (vi) provides printouts. Because RAP can import files, it can analyze not only bioluminescence data but also other data such as those obtained by DNA array experiments and by Northern and Western blot analyses. The program is a powerful tool for large-scale investigations of biological rhythmic phenomena in general.

Arabidopsis↗

PubMed2006

Rap-GEF signaling controls stem cell anchoring to their niche through regulating DE-cadherin-mediated cell adhesion in the Drosophila testis.

Stem cells will undergo self-renewal to produce new stem cells if they are maintained in their niches. The regulatory mechanisms that recruit and maintain stem cells in their niches are not well understood. In Drosophila testes, a group of 12 nondividing somatic cells, called the hub, identifies the stem cell niche by producing the growth factor Unpaired (Upd). Here, we show that Rap-GEF/Rap signaling controls stem cell anchoring to the niche through regulating DE-cadherin-mediated cell adhesion. Loss of function of a Drosophila Rap-GEF (Gef26) results in loss of both germline and somatic stem cells. The Gef26 mutation specifically impairs adherens junctions at the hub-stem cell interface, which results in the stem cells "drifting away" from the niche and losing stem cell identity. Thus, the Rap signaling/E-cadherin pathway may represent one mechanism that regulates polarized niche formation and stem cell anchoring.

Animals↗

PubMed2006

Synthesis, interaction with double-helical DNA and biological activity of the water soluble complex cis-dichloro-1,2-propylenediamine-N,N,N',N'-tetraacetato ruthenium (III) (RAP).

The effects exerted by the new complex cis-dichloro-1,2-propylenediaminetetraacetato ruthenium (III), H[RuCl(2)(PDTA-H(2))] [1, RAP], on DNA and cultured tumor cells (ovarian carcinoma TG cell line) were studied. The comparative study of circular dichroism (CD) spectra obtained from DNA and RAP-DNA system evidences the interaction of the complex with DNA. Compound 1 also interacted with tumor TG cells to slow their proliferation rate. BrdU incorporation was enhanced in cells treated with compound 1, as evidenced by a single-cell electrophoresis method (comet assay), in accordance with RAP-induced DNA damage. DNA migration of compound 1-treated cells was similar to that induced by noxious agents other than cross-linking chemicals. The stability of [RuCl(2)(PDTA-H(2))]-DNA binding is suggested by the high degree of damage that persisted after removal of compound 1 from the culture medium.

Antineoplastic Agents↗

PubMed2006

Binding site structure of one LRP-RAP complex: implications for a common ligand-receptor binding motif.

The low-density lipoprotein receptor-related protein (LRP) interacts with more than 30 ligands of different sizes and structures that can all be replaced by the receptor-associated protein (RAP). The double module of complement type repeats, CR56, of LRP binds many ligands including all three domains of RAP and alpha2-macroglobulin, which promotes the catabolism of the Abeta-peptide implicated in Alzheimer's disease. To understand the receptor-ligand cross-talk, the NMR structure of CR56 has been solved and ligand binding experiments with RAP domain 1 (RAPd1) have been performed. From chemical shift perturbations of both binding partners upon complex formation, a HADDOCK model of the complex between CR56 and RAPd1 has been obtained. The binding residues are similar to a common binding motif suggested from alpha2-macroglobulin binding studies and provide evidence for an understanding of their mutual cross-competition pattern. The present structural results convey a simultaneous description of both binding partners of an LRP-ligand complex and open a route to a broader understanding of the binding specificity of the LRP receptor, which may involve a general four-residue receptor-ligand recognition motif common to all LRP ligands. The present result may be beneficial in the design of antagonists of ligand binding to the LDL receptor family, and especially of drugs for treatment of Alzheimer's disease.

Amino Acid Motifs↗

PubMed2006

Structure of an LDLR-RAP complex reveals a general mode for ligand recognition by lipoprotein receptors.

Proteins of the low-density lipoprotein receptor (LDLR) family are remarkable in their ability to bind an extremely diverse range of protein and lipoprotein ligands, yet the basis for ligand recognition is poorly understood. Here, we report the 1.26 A X-ray structure of a complex between a two-module region of the ligand binding domain of the LDLR and the third domain of RAP, an escort protein for LDLR family members. The RAP domain forms a three-helix bundle with two docking sites, one for each LDLR module. The mode of recognition at each site is virtually identical: three conserved, calcium-coordinating acidic residues from each LDLR module encircle a lysine side chain protruding from the second helix of RAP. This metal-dependent mode of electrostatic recognition, together with avidity effects resulting from the use of multiple sites, represents a general binding strategy likely to apply in the binding of other basic ligands to LDLR family proteins.

Amino Acid Sequence↗

PubMed1998

RAP, a novel type of ER chaperone.

Members of the low-density lipoprotein (LDL) receptor gene family play an important role in cellular uptake of various extracellular ligands. Recent studies have shown that a 39-kDa protein known as RAP (receptor-associated protein) serves as a molecular chaperone to assist the folding of certain LDL-receptor family proteins and their passage through the secretory pathway. In this review, the authors discuss our current understanding of the roles of RAP as a molecular chaperone/escort protein and present a model of how RAP might carry out these functions.

Carrier Proteins↗

PubMed2006

Macular atrophy after combined intravitreal triamcinolone acetonide (IVTA) and photodynamic therapy (PDT) for retinal angiomatous proliferation (RAP).

BACKGROUND: Retinal angiomatous proliferation (RAP) is a variant of exudative AMD that appears to respond poorly to standard PDT. This pilot study explores the potential efficacy and safety of combined intravitreal triamcinolone acetonide (IVTA). PATIENTS AND METHODS: In a prospective interventional case series 10 eyes of 8 patients with RAP were treated with combined IVTA/PDT. RESULTS: After 3 months there was no evidence of significant exudative activity in 7/10 eyes treated with IVTA/PDT, three eyes required re-treatment. After 6 months 4/10 eyes were "dry" on fluorescein angiography, visual acuity was stable (loss of less than 3 Snellen lines) or had improved in 5/10 eyes. 5/10 eyes had lost 3 or more lines, due to central macular atrophy in 4/5 eyes and secondary to a progressive exudative lesion in 1/5 eyes. CONCLUSIONS: Intravitreal steroids combined with PDT appear to be a step ahead in the treatment of RAP. Our results, however, raise the question whether combined treatment may create more atrophy leading to vision loss in some cases.

Aged↗

PubMed1998

Rapping, a female receptive call, initiates male-female duets in the South African clawed frog.

Finding a sexually receptive partner of the opposite sex is a challenge; one solution is to advertise. That advertising is usually the province of males has shaped scenarios for sexual selection, especially the ardent active male courting the passive but choosy female. Herein we consider an unusual case in which constraints on reproduction may have led to fertility advertisement by female frogs. When oviposition is imminent, female South African clawed frogs swim to an advertising male and produce an aphrodisiac call, rapping, that stimulates both male vocalization and approach. Males respond to rapping with a distinctive answer call. The rapping-answer interaction thus forms a duet between partners of a receptive pair.

Animals↗

PubMed2001

Identification and characterization of RA-GEF-2, a Rap guanine nucleotide exchange factor that serves as a downstream target of M-Ras.

The Ras family small GTPase Rap is regulated by an array of specific guanine nucleotide exchange factors (GEFs) in response to upstream stimuli. RA-GEF-1 was identified as a novel Rap GEF, which possesses a Ras/Rap1-associating (RA) domain. Here we report a protein closely related to RA-GEF-1, named RA-GEF-2. Like RA-GEF-1, a putative cyclic nucleotide monophosphate-binding domain, a Ras exchanger motif, a PSD-95/DlgA/ZO-1 domain, and an RA domain in addition to the GEF catalytic domain are found in RA-GEF-2. However, RA-GEF-2 displays a different tissue distribution profile from that of RA-GEF-1. RA-GEF-2 stimulates guanine nucleotide exchange of both Rap1 and Rap2, but not Ha-Ras. The RA domain of RA-GEF-2 binds to M-Ras in a GTP-dependent manner, but not to other Ras family GTPases tested, including Ha-Ras, N-Ras, Rap1A, Rap2A, R-Ras, RalA, Rin, Rit, and Rheb, in contrast to the RA domain of RA-GEF-1, which specifically binds to Rap1. In accordance with this, RA-GEF-2 colocalizes with activated M-Ras in the plasma membrane in COS-7 cells, suggesting a role of RA-GEF-2 in the regulation of Rap1 and Rap2, particularly in the plasma membrane. In fact, an increase in the level of the GTP-bound form of plasma membrane-located Rap1 was observed when coexpressed with RA-GEF-2 and activated M-Ras. Thus, RA-GEF-2 acts as a GEF for Rap1 and Rap2 downstream of M-Ras in the plasma membrane, whereas RA-GEF-1 exerts Rap GEF function in perinuclear compartments including the Golgi apparatus.

Amino Acid Sequence↗

PubMed2006

The Rice Annotation Project Database (RAP-DB): hub for Oryza sativa ssp. japonica genome information.

With the completion of the rice genome sequencing, a standardized annotation is necessary so that the information from the genome sequence can be fully utilized in understanding the biology of rice and other cereal crops. An annotation jamboree was held in Japan with the aim of annotating and manually curating all the genes in the rice genome. Here we present the Rice Annotation Project Database (RAP-DB), which has been developed to provide access to the annotation data. The RAP-DB has two different types of annotation viewers, BLAST and BLAT search, and other useful features. By connecting the annotations to other rice genomics data, such as full-length cDNAs and Tos17 mutant lines, the RAP-DB serves as a hub for rice genomics. All of the resources can be accessed through http://rapdb.lab.nig.ac.jp/.

Databases, Nucleic Acid↗

PubMed2002

Power of shell-rapping signals influences physiological costs and subsequent decisions during hermit crab fights.

Understanding the costs of signals used in fights is the key to understanding decisions made by contestants. Hermit crabs use shell rapping. This is a clearly defined agonistic signal, which can be quantified in temporal terms and in the power of the key shell-rapping signal component. We examine the relationship between the power expended by attacking hermit crabs and their consequent lactate levels. High power expenditure over the whole fight leads to high lactate, and attackers give up when lactate is high. Some defenders give up early in fights, particularly if the power of raps in early bouts they receive is high. These defenders and those not allowed to fight have low glucose, but those that successfully resist eviction have high glucose. Glucose is mobilized in an attempt to resist; nevertheless, some defenders that attempt resistance are still evicted by persistent attackers. Thus, early power of the signal is a major determinant of success for attackers, albeit at a cost. These data show the link between power, repetition of a signal, metabolic consequences and decisions of contestants in fights. The different activities, decisions and costs of the two roles are not adequately described by existing models of contests.

Aggression↗

PubMed1988

ras p21 oncoprotein expression in human colonic neoplasia--an immunohistochemical study with monoclonal antibody RAP-5.

Expression of the ras oncogene product p21 (ras p21) in benign and malignant human colonic tissues was studied using the monoclonal antibody RAP-5 and the avidin-biotin-peroxidase technique. Histologically normal colonic mucosa and hyperplastic mucosa adjacent to carcinomas (transitional mucosa) were found, in most cases, to be negative for reactivity with the antibody or showed weak staining of a few epithelial cells. Similar findings were observed in hyperplastic and juvenile polyps. Of the 145 adenomas studied, 47 (32.4%) showed detectable levels of ras p21 expression. RAP-5 immunohistochemical staining was significantly associated with the degree of epithelial dysplasia (P less than 0.01) and the size of adenoma (P less than 0.05), but not with the histological type. Fifty-four of 70 primary adenocarcinomas (77.1%) were reactive with RAP-5 and usually demonstrated a higher percentage of stained cells and more intense cytoplasmic staining than that observed in adenomas. Although metastases often displayed a similar or even higher levels of ras p21 expression compared with the primary carcinomas, in 10 cases one or more metastatic lesions showed lower levels of ras p21. These results suggest that enhanced ras p21 expression may, at times, occur in the early stages of human colon carcinogenesis but are probably not associated with metastatic tumour progression.

Adenocarcinoma↗