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PubMed2005

Synergistic regulation of competence development in Bacillus subtilis by two Rap-Phr systems.

The 11 Rap proteins of Bacillus subtilis comprise a conserved family of tetratricopeptide (TPR)-containing regulatory proteins. Their activity is inhibited by specific Phr pentapeptides produced from the product of phr genes through an export-import maturation process. We found that one of the proteins, namely RapF, is involved in the regulation of competence to DNA transformation. The ComA response regulator and transcription factor for initiation of competence development is the target of RapF. Specific binding of RapF to the carboxy-terminal DNA-binding domain of ComA inhibits the response regulator's ability to bind its target DNA promoters. The PhrF C-terminal pentapeptide, QRGMI, inhibits RapF activity. The activity of RapF and PhrF in regulating competence development is analogous to the previously described activity of RapC and PhrC (L. J. Core and M. Perego, Mol. Microbiol. 49:1509-1522, 2003). In fact, the RapF and PhrF pair of proteins acts synergistically with RapC and PhrC in the overall regulation of the ComA transcription factor. Since the transcription of the RapC- and RapF-encoding genes is positively regulated by their own target ComA, an autoregulatory circuit must exist for the competence transcription factor in order to modulate its activity.

Amino Acid Sequence↗
PubMed2002

Rebellious Rhapsody: Metal, Rap, Community, and Individuation.

Music can be a powerful force and tool in the life of an adolescent. It forms a social context and informs the adolescent about the adult world through the lens of artists' lives, language, and presence as models. Allegiance to a form of music is allegiance to those who make it, a way to friendship and kinship, and a road to personal identity through belonging. In their relationships formed through music, teens can create a sense of community that may be lacking in the life of family. The rebellious music of earlier generations has given rise to complex musical genres, rap and heavy metal, that are strong in defiance and controversial in their violent and sexual content. What do these musical affiliations tell us about certain segments of adolescent development and culture? The authors consider this question by exploring the form and content of the music while using it to illuminate psychodynamic and psychosocial aspects of adolescent development.

Journal Article↗
PubMed1988

Prospective payment for physician services: a "RAP" (radiology, anesthesiology, pathology) on the future.

Development of a prospective payment system for physician services under Medicare and Medicaid is still being considered in Washington. The first step will be to "bundle" radiology, anesthesiology and pathology ("RAP") services into existing Medicare DRG schedules. Other hospital-based physician services, including surgery and medical management, may also be included.

Anesthesiology↗
PubMed2004

RNA fingerprinting using RAP-PCR identifies an EBAF homologue mRNA differentially expressed in rat oviduct.

As a step towards the identification of genes preferentially expressed in the oviduct during early rat embryo development, we isolated a cDNA fragment (Pr14) by using RNA arbitrarily primed PCR (RAP-PCR), being its expression restricted to oviduct and uterus; its mRNA is mainly expressed in oviduct during late luteal phase and early pregnancy. This fragment is 100% identical to a rat DNA sequence (Accession No. NW_047400) downstream the terminal exon of a Ratturs norvegicus gene (Locus Link Accession No. LOC289316) similar to ebaf (endometrial bleeding-associated factor), a novel member of the Transforming Growth Factor superfamily. Northern analyses showed that this sequence hybridizes with 2.9 kb and 4.1 kb mRNAs in early pregnant rat oviducts. However, only the 4.1 kb mRNA was detected in the oviduct of non-pregnant rats, showing an increase from proestrus to diestrus. The expression of this oviduct-uterus specific mRNA suggests that the products of this gene may play a role in the oviductal reproductive process.

Animals↗
PubMed1991

The residues of Ras and Rap proteins that determine their GAP specificities.

The oncogenic transformation of a normal fibroblast by mutated Ras genes can be reversed by overexpression of a Ras-related gene called Rap1A (or Krev1). Both Ras and Rap1A proteins are G proteins and appear to serve as signal transducers only in the GTP-bound form. Therefore, GAP1 and GAP3, which stimulate the intrinsic GTPase activities of normal Ras and Rap1A proteins, respectively, serve as attenuators of their signal transducing activities. In this paper, we describe the enzymatic properties of several mutated Rap1A and chimeric Ras/Rap1A (or -1B) proteins which lead to the following conclusions: (i) the GAP3-dependent activation of both Rap1A and -1B GTPases requires Gly12, but neither Thr61 nor Gln63; (ii) residues 64 to 70 of the Rap1 GTPases are sufficient to determine their specificities for GAP3; and (iii) residues 61 to 65 of the Ras GTPases are sufficient for determining their specificities for GAP1. Thus, the domains of the Ras or Rap1 proteins that determine whether their signals are attenuated by GAP1 or GAP3 are distinct from the N-terminal domain (residues 21 to 54) that determines whether their signals are oncogenic or antioncogenic. The Arg12 mutant of chimeric HaRas(1-54)/Rap1A(55-184) protein has been previously reported to be oncogenic (Zhang, K., Noda, M., Vass, W. C., Papageorge, A.G., and Lowy, D.R. (1990) Science 249, 162-165). In this paper, we show that the Val12 mutant of chimeric HaRas(1-54)/Rap1B(55-184) protein is also oncogenic, suggesting that the C-terminal geranylgeranylation of the Rap 1B protein can replace functionally the C-terminal farnesylation of the Ras protein to allow the G protein to be oncogenic.

Amino Acid Sequence↗
PubMed1991

The Drosophila roughened mutation: activation of a rap homolog disrupts eye development and interferes with cell determination.

Roughened is a dominant mutation of D. melanogaster that disrupts eye development. The majority of the ommatidia in the adult eye lack a single photoreceptor cell, which is most commonly the R7 cell. The Roughened mutation disrupts the early stages of photoreceptor cell determination. Roughened is a dominant gain-of-function mutation that results from a single amino acid change (Phe157 to Leu) in the Drosophila Rap1 protein. Loss of function Rap1 mutations are lethal. Drosophila Rap1 protein is 88% identical to human rap1A/K-rev1 protein, a putative antagonist of ras action.

Amino Acid Sequence↗
PubMed2005

Analysis of Ras and Rap activation in living cells using fluorescent Ras binding domains.

Ras GTPases regulate cellular growth and differentiation and are modulated by myriad stimuli including growth factors, cytokines, antigens, and UV irradiation. Ras GTPases are molecular switches that are active when GTP-bound and inactive when GDP-bound. The ability of these GTPases to signal requires that the GTP-bound form engage downstream effectors, interactions that occur only on the cytosolic surface of cellular membranes. Ras family proteins include H-Ras, N-Ras, K-Ras, and Rap1. Insight into the regulation and signaling properties of these molecules has come largely from in vitro studies relying on cellular extracts prepared following cellular stimulation. Since Ras GTPases are expressed on multiple cellular compartments that include the plasma membrane, vesicles derived from the plasma membrane, and other internal membranes such as the ER and Golgi complex, analysis of how their spatial distribution modulates signaling has remained unknown. We have developed fluorescent, GFP-based probes capable of selectively binding GTP-bound Ras or Rap1 in living cells. We have used these reporters to examine sites of cellular activation of Ras and Rap1 during growth factor stimulation. These studies have revealed new insights into the platforms from which these GTPases signal and have led to the hypothesis that GTPase signaling is modulated in a compartmentalized fashion. Here, we describe the design and implementation of fluorescent probes for Ras and Rap1.

Animals↗
PubMed2006

Characterization of the activation of the Rap-specific exchange factor Epac by cyclic nucleotides.

Epac1 and Epac2 are cAMP-dependent guanine nucleotide exchange factors (GEF) for the small G-proteins Rap1 and Rap2. Epac is inactive in the absence of cAMP, and binding of cAMP to a cyclic nucleotide-binding domain in the N-terminal regulatory region results in activation of the protein. The cAMP-dependent activity of Epac proteins can be analyzed by a fluorescence-based assay in vitro. These kinds of measurements can help to unravel the molecular mechanism by which cAMP binding is translated in activation of the protein. For this purpose, Epac mutants can be analyzed. In addition, the interaction of cAMP itself might be the focus of the research. Thus, modified cAMP analogs can be characterized by their ability to activate Epac. This is of particular interest for the development of Epac-specific analogs, which do not act on other cellular cAMP targets such as protein kinase A (PKA) or for the design of therapeutic agents targeting Epac.

Cyclic AMP↗
PubMed1995

Purification of human neutrophil NADPH oxidase cytochrome b-558 and association with Rap 1A.

The availability of sufficient quantities of highly purified phagocyte cytochrome b-558 has been necessary for many of the biochemical and immunological analyses of this important NADPH oxidase component, and it was only through the analysis of highly purified cytochrome b that the subunit composition was elucidated and the small subunit (p22-phox) was cloned and sequenced. In addition, the association of the small GTP-binding protein Rap1A with cytochrome b-558 was discovered through the analysis of purified cytochrome b. The procedures described here provide an easy, efficient, and highly reproducible method for the purification of cytochrome b as well as cytochrome b-Rap1A complexes. The ability to purify cytochrome b and cytochrome b-Rap1A complexes will also allow further analysis of the structure of this novel plasma membrane redox protein and the role of its association with low molecular weight GTP-binding proteins in the structure and regulation of the phagocyte NADPH oxidase.

Cell Membrane↗
PubMed2005

Trading spaces: Rap, Rac, and Rho as architects of transendothelial migration.

PURPOSE OF REVIEW: This review focuses on recent developments in understanding regulation of leukocyte transendothelial migration by small GTPase signaling. RECENT FINDINGS: New studies are refining the model for GTPase regulation of leukocyte-endothelial cell interactions that occur during leukocyte transmigration. An emerging theme is that the endothelial cell is an active participant in this process; an example of this is the identification of a novel leukocyte docking structure. The role of second messengers such as reactive oxygen species downstream and the involvement of kinases such as Pyk2 and Tec kinases upstream of GTPase activation is becoming appreciated. In the leukocyte, finer distinctions between closely related GTPases like Rac1 and Rac2 are being made, and a new role for RhoH has been characterized. Finally, the focus on Rap1 as a key regulator of leukocyte integrin-dependent adhesion is expanding to include roles in endothelial cell-cell adhesion and junctional regulation during transmigration. SUMMARY: Understanding the complex series of events involved in cell-cell interactions during leukocyte transendothelial migration is a prerequisite for designing novel therapies to treat clinical conditions in which an inappropriate inflammatory response leads to disease. A discussion is provided of recent developments in the molecular regulation of leukocyte recruitment.

Animals↗
PubMed1996

Silencing of genes at nontelomeric sites in yeast is controlled by sequestration of silencing factors at telomeres by Rap 1 protein.

Rap1p binds to silencer elements and telomeric repeats in yeast, where it appears to initiate silencing by recruiting Sir3p and Sir4p to the chromosome through interactions with its carboxy-terminal domain. Sir3p and Sir4p interact in vitro with histones H3 and H4 and are likely to be structural components of silent chromatin. We show that targeting of these Sir proteins to the chromosome is sufficient to initiate stable silencing either at a silent mating-type locus lacking a functional silencer element or at a telomere in a strain in which the Rap1p carboxy-terminal silencing domain has been deleted. Silencing by Sir protein targeting can also be initiated at a telomere-proximal site (ADH4), but is much weaker at an internal chromosomal locus (LYS2). Strikingly, deletion of the Rap1p silencing domain, which abolishes telomeric silencing, improves targeted silencing at LYS2 by both Sir3p and Sir4p, while weakening the silencing activity of these proteins at or near a telomere. This effect may result from the release of Sir proteins from the telomeres, thus increasing their effective concentration at other chromosomal sites. We suggest that telomeres and Rap1p serve a regulatory role in sequestering Sir proteins at telomeres, controlling silencing at other loci in trans and preventing indiscriminate gene silencing throughout the genome.

Chromosomes, Fungal↗
PubMed1992

Generation of specific antibodies against the rap1A, rap1B and rap2 small GTP-binding proteins. Analysis of rap and ras proteins in membranes from mammalian cells.

Specific antibodies against rap1A and rap1B small GTP-binding proteins were generated by immunization of rabbits with peptides derived from the C-terminus of the processed proteins. Immunoblot analysis of membranes from several mammalian cell lines and human thrombocytes with affinity-purified antibodies against rap1A or rap1B demonstrated the presence of multiple immunoreactive proteins in the 22-23 kDa range, although at strongly varying levels. Whereas both proteins were present in substantial amounts in membranes from myelocytic HL-60, K-562 and HEL cells, they were hardly detectable in membranes from lymphoma U-937 and S49.1 cyc- cells. Membranes from human thrombocytes and 3T3-Swiss Albino fibroblasts showed strong rap1B immunoreactivity, whereas rap1A protein was present in much lower amounts. In the cytosol of HL-60 cells, only small amounts of rap1A and rap1B proteins were detected, unless the cells were treated with lovastatin, an inhibitor of hydroxymethylglutaryl-coenzyme A reductase, suggesting that both proteins are isoprenylated. By comparison with recombinant proteins, the ratio of rap1A/ras proteins in membranes from HL-60 cells was estimated to be about 4:1. An antiserum directed against the C-terminus of rap2 reacted strongly with recombinant rap2, but not with membranes from tested mammalian cells. In conclusion, rap1A and rap1B proteins are distributed differentially among membranes from various mammalian cell types and are isoprenylated in HL-60 cells.

Amino Acid Sequence↗