Genomes and Genes
ras guanine nucleotide exchange factors
Summary: A family of GUANINE NUCLEOTIDE EXCHANGE FACTORS that are specific for RAS PROTEINS.
- Yang Y, Li L, Wong G, Krilis S, Madhusudhan M, Sali A, et al. RasGRP4, a new mast cell-restricted Ras guanine nucleotide-releasing protein with calcium- and diacylglycerol-binding motifs. Identification of defective variants of this signaling protein in asthma, mastocytosis, and mast cell leukemia patients and . J Biol Chem. 2002;277:25756-74 pubmed..HMC-1 leukemia cells differentiated and underwent granule maturation when induced to express a normal form of RasGRP4. Thus, RasGRP4 plays an important role in the final stages of MC development...
- Ye B, Liao D, Zhang X, Zhang P, Dong H, Huganir R. GRASP-1: a neuronal RasGEF associated with the AMPA receptor/GRIP complex. Neuron. 2000;26:603-17 pubmed..These results suggest that GRASP-1 may regulate neuronal ras signaling and contribute to the regulation of AMPA receptor distribution by NMDA receptor activity. ..
- Chen H, Suzuki M, Nakamura Y, Ohira M, Ando S, Iida T, et al. Aberrant methylation of RASGRF2 and RASSF1A in human non-small cell lung cancer. Oncol Rep. 2006;15:1281-5 pubmed..Frequent methylation and silencing of RASGRF2 in tumor cells may play an important role, different from that of RASSF1A, in the carcinogenesis of NSCLC. ..
- Kortholt A, Rehmann H, Kae H, Bosgraaf L, Keizer Gunnink I, Weeks G, et al. Characterization of the GbpD-activated Rap1 pathway regulating adhesion and cell polarity in Dictyostelium discoideum. J Biol Chem. 2006;281:23367-76 pubmed..Phg2, a serine/threonine-specific kinase, directly interacts with Rap1 via its Ras association domain. ..
- Geyer M, Wittinghofer A. GEFs, GAPs, GDIs and effectors: taking a closer (3D) look at the regulation of Ras-related GTP-binding proteins. Curr Opin Struct Biol. 1997;7:786-92 pubmed..Recently, a large number of genes encoding GTP-binding proteins and the proteins that interact with these molecular switches have been cloned and expressed. The 3D structures of some of these have also been elucidated. ..
- Simon M, Bowtell D, Dodson G, Laverty T, Rubin G. Ras1 and a putative guanine nucleotide exchange factor perform crucial steps in signaling by the sevenless protein tyrosine kinase. Cell. 1991;67:701-16 pubmed..These results suggest that the stimulation of ras protein activity is a key element in the signaling by sevenless and Ellipse and that this stimulation may be achieved by activating the exchange of GTP for bound GDP by the ras protein. ..
- Cherfils J, Chardin P. GEFs: structural basis for their activation of small GTP-binding proteins. Trends Biochem Sci. 1999;24:306-11 pubmed..These structures, together with biochemical studies, have allowed a deeper understanding of the mechanisms of activation of Ras-like GTP-binding proteins and suggested how they might represent targets for therapeutic intervention. ..
- Wilkins A, Szafranski K, Fraser D, Bakthavatsalam D, Muller R, Fisher P, et al. The Dictyostelium genome encodes numerous RasGEFs with multiple biological roles. Genome Biol. 2005;6:R68 pubmed..These results suggest that the unexpectedly large number of RasGEF genes reflects an evolutionary expansion of the range of Ras signaling rather than functional redundancy or the presence of multiple pseudogenes. ..
- Tian X, Gotoh T, Tsuji K, Lo E, Huang S, Feig L. Developmentally regulated role for Ras-GRFs in coupling NMDA glutamate receptors to Ras, Erk and CREB. EMBO J. 2004;23:1567-75 pubmed..Interestingly, in cortical neurons of neonatal animals NMDARs signal through Sos rather than Ras-GRF exchange factors, implying that Ras-GRFs endow NMDARs with functions unique to mature neurons. ..
- Forlani G, Baldassa S, Lavagni P, Sturani E, Zippel R. The guanine nucleotide exchange factor RasGRF1 directly binds microtubules via DHPH2-mediated interaction. FEBS J. 2006;273:2127-38 pubmed..Identification of microtubules as new binding partners of RasGRF1 may help to elucidate the signaling network in which RasGRF1 is involved. ..
- Gotoh T, Hattori S, Nakamura S, Kitayama H, Noda M, Takai Y, et al. Identification of Rap1 as a target for the Crk SH3 domain-binding guanine nucleotide-releasing factor C3G. Mol Cell Biol. 1995;15:6746-53 pubmed..Furthermore, expression of C3G with a membrane localization signal in a v-Ki-ras transformant, DT, induced a reversion of the cells to the flat form, possibly through the activation of endogenous Rap1. ..
- Wilkins A, Chubb J, Insall R. A novel Dictyostelium RasGEF is required for normal endocytosis, cell motility and multicellular development. Curr Biol. 2000;10:1427-37 pubmed..RasGEFB appears to be the principal activator of the RasS protein, which regulates macropinocytosis and cell speed, but it also appears to regulate one or more other Ras proteins. ..
- Ruiz S, Santos E, Bustelo X. RasGRF2, a guanosine nucleotide exchange factor for Ras GTPases, participates in T-cell signaling responses. Mol Cell Biol. 2007;27:8127-42 pubmed..These results identify RasGRF2 as an additional component of the signaling machinery involved in T-cell receptor- and NF-AT-mediated immune responses. ..
- Katsoulotos G, Qi M, Qi J, Tanaka K, Hughes W, Molloy T, et al. The Diacylglycerol-dependent translocation of ras guanine nucleotide-releasing protein 4 inside a human mast cell line results in substantial phenotypic changes, including expression of interleukin 13 receptor alpha2. J Biol Chem. 2008;283:1610-21 pubmed
- Chubb J, Insall R. Dictyostelium: an ideal organism for genetic dissection of Ras signalling networks. Biochim Biophys Acta. 2001;1525:262-71 pubmed..This review highlights the recent advances in our understanding of Ras function in Dictyostelium, and considers the implications of these findings for our understanding of eukaryotic signal transduction. ..
- Kadowaki T, Goldfarb D, Spitz L, Tartakoff A, Ohno M. Regulation of RNA processing and transport by a nuclear guanine nucleotide release protein and members of the Ras superfamily. EMBO J. 1993;12:2929-37 pubmed..Thus, MTR1 and its homologs appear to act as GNRPs for a family of conserved GTPases in controlling RNA metabolism and transport. Their role in governing checkpoint control appears to be restricted to higher eukaryotes. ..
- Farnsworth C, Freshney N, Rosen L, Ghosh A, Greenberg M, Feig L. Calcium activation of Ras mediated by neuronal exchange factor Ras-GRF. Nature. 1995;376:524-7 pubmed..So far, full-length Ras-GRF has been detected only in brain neurons. Our findings implicate Ras-GRF in the regulation of neuronal functions that are influenced by Ca2+ signals. ..
- Huang J, Furuya A, Furuichi T. Very-KIND, a KIND domain containing RasGEF, controls dendrite growth by linking Ras small GTPases and MAP2. J Cell Biol. 2007;179:539-52 pubmed..These findings suggest that v-KIND mediates a signaling pathway that links Ras and MAP2 to control dendrite growth. ..
- Yaman E, Gasper R, Koerner C, Wittinghofer A, Tazebay U. RasGEF1A and RasGEF1B are guanine nucleotide exchange factors that discriminate between Rap GTP-binding proteins and mediate Rap2-specific nucleotide exchange. FEBS J. 2009;276:4607-16 pubmed publisher..Mutation of the corresponding Ser39 in Rap1 changed the specificity and allowed the nucleotide exchange of Rap1(S39F) to be stimulated by RasGEF1B. ..
- Zhu M, Fuller D, Zhang W. The role of Ras guanine nucleotide releasing protein 4 in Fc epsilonRI-mediated signaling, mast cell function, and T cell development. J Biol Chem. 2012;287:8135-43 pubmed publisher..Our data suggest that after the engagement of immunoreceptors, immune cells likely employ multiple members of the RasGRP family to transduce critical signals. ..
- Bosgraaf L, Waijer A, Engel R, Visser A, Wessels D, Soll D, et al. RasGEF-containing proteins GbpC and GbpD have differential effects on cell polarity and chemotaxis in Dictyostelium. J Cell Sci. 2005;118:1899-910 pubmed..GbpD induces the formation of substrate-attached pseudopodia, resulting in increased attachment and suppression of polarity. ..
- Heo J, Campbell S. Ras regulation by reactive oxygen and nitrogen species. Biochemistry. 2006;45:2200-10 pubmed..However, given the lack of redox specificity associated with the high redox potential of OH(*), it is unclear whether this reaction occurs under physiological conditions. ..
- Kae H, Kortholt A, Rehmann H, Insall R, Van Haastert P, Spiegelman G, et al. Cyclic AMP signalling in Dictyostelium: G-proteins activate separate Ras pathways using specific RasGEFs. EMBO Rep. 2007;8:477-82 pubmedIn general, mammalian Ras guanine nucleotide exchange factors (RasGEFs) show little substrate specificity, although they are often thought to regulate specific pathways...
- de Rooij J, Zwartkruis F, Verheijen M, Cool R, Nijman S, Wittinghofer A, et al. Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP. Nature. 1998;396:474-7 pubmed..cAMP strongly induces the GEF activity of Epac towards Rap1 both in vivo and in vitro. We conclude that Epac is a GEF for Rap1 that is regulated directly by cAMP and that Epac is a new target protein for cAMP. ..
- Lee S, Parent C, Insall R, Firtel R. A novel Ras-interacting protein required for chemotaxis and cyclic adenosine monophosphate signal relay in Dictyostelium. Mol Biol Cell. 1999;10:2829-45 pubmed
- Chardin P, Camonis J, Gale N, Van Aelst L, Schlessinger J, Wigler M, et al. Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2. Science. 1993;260:1338-43 pubmed..These results suggest that the coupling of receptor tyrosine kinases to Ras signaling is mediated by a molecular complex consisting of GRB2 and hSos1. ..
- Ichiba T, Hoshi Y, Eto Y, Tajima N, Kuraishi Y. Characterization of GFR, a novel guanine nucleotide exchange factor for Rap1. FEBS Lett. 1999;457:85-9 pubmed..Northern blot analysis suggested that GFR mRNA is strongly expressed in the brain. In transfected HeLa cells, GFR has been found to be localized in the nuclei. ..
- Heo J, Prutzman K, Mocanu V, Campbell S. Mechanism of free radical nitric oxide-mediated Ras guanine nucleotide dissociation. J Mol Biol. 2005;346:1423-40 pubmed..This mechanism is likely to be common to other NKCD motif-containing Ras superfamily GTPases, as NO/O2 also facilitates GNE on the redox-active Rap1A and Rab3A GTPases. ..
- Geymonat M, Wang L, Garreau H, Jacquet M. Ssa1p chaperone interacts with the guanine nucleotide exchange factor of ras Cdc25p and controls the cAMP pathway in Saccharomyces cerevisiae. Mol Microbiol. 1998;30:855-64 pubmed..Altogether, these results lead to the conclusion that Ssa1p positively controls the cAMP pathway through Cdc25p. We propose that this connection plays a critical role in the adaptation of cells to stress conditions. ..
- King J, Insall R. Parasexual genetics of Dictyostelium gene disruptions: identification of a ras pathway using diploids. BMC Genet. 2003;4:12 pubmed..They will particularly facilitate generation of multiple mutants and manipulation of essential genes. ..
- Randhawa P, Rylova S, Heinz J, Kiser S, Fried J, Dunworth W, et al. The Ras activator RasGRP3 mediates diabetes-induced embryonic defects and affects endothelial cell migration. Circ Res. 2011;108:1199-208 pubmed publisher..RasGRP3 may be a novel therapeutic target for the fetal complications of diabetes. ..
- Suzuki C, Takahashi K, Hayama S, Ishikawa N, Kato T, Ito T, et al. Identification of Myc-associated protein with JmjC domain as a novel therapeutic target oncogene for lung cancer. Mol Cancer Ther. 2007;6:542-51 pubmed
- Ye B, Sugo N, Hurn P, Huganir R. Physiological and pathological caspase cleavage of the neuronal RasGEF GRASP-1 as detected using a cleavage site-specific antibody. Neuroscience. 2002;114:217-27 pubmed..It also demonstrates that the CGP antibody is a powerful tool for studying neuronal activity of the caspase-3-subfamily caspases in vivo. ..
- Stevens R, Morokawa N, Wang J, Krilis S. RasGRP4 in mast cell signalling and disease susceptibility. Novartis Found Symp. 2005;271:54-68; discussion 68-77, 95-9 pubmed..These and other data suggest that RasGRP4 is of critical importance in mast cell development and that the expression of abnormal isoforms of the protein can lead to mast cell dysfunction. ..
- Chin H, Saito T, Arai A, Yamamoto K, Kamiyama R, Miyasaka N, et al. Erythropoietin and IL-3 induce tyrosine phosphorylation of CrkL and its association with Shc, SHP-2, and Cbl in hematopoietic cells. Biochem Biophys Res Commun. 1997;239:412-7 pubmed..These results suggest that CrkL is involved in the signaling pathways from the receptors for Epo and IL-3, most likely by modulating the activity of the Ras family GTPases through its interaction with C3G. ..
- Korotayev K, Chaussepied M, Ginsberg D. ERK activation is regulated by E2F1 and is essential for E2F1-induced S phase entry. Cell Signal. 2008;20:1221-6 pubmed publisher..Our results indicate that the relationship between these signaling modules is not a simple unidirectional linear one and suggests there exists a positive feedback loop that may enhance both ERK signaling and E2F1 activity. ..
- Nakamura S, Takemura T, Tan L, Nagata Y, Yokota D, Hirano I, et al. Small GTPase RAB45-mediated p38 activation in apoptosis of chronic myeloid leukemia progenitor cells. Carcinogenesis. 2011;32:1758-72 pubmed publisher..Our results identify a new signaling molecule involved in BCR-ABL modulation of apoptosis and suggest that RAB45 induction strategies may have therapeutic utility in patients with CML. ..
- Rubio I, Grund S, Song S, Biskup C, Bandemer S, Fricke M, et al. TCR-induced activation of Ras proceeds at the plasma membrane and requires palmitoylation of N-Ras. J Immunol. 2010;185:3536-43 pubmed publisher..These findings identify the PM as the only site of TCR-driven Ras activation and document that endomembranes are not a signaling platform for Ras in T cells. ..
- Schwechter B, Rosenmund C, Tolias K. RasGRF2 Rac-GEF activity couples NMDA receptor calcium flux to enhanced synaptic transmission. Proc Natl Acad Sci U S A. 2013;110:14462-7 pubmed publisher..Because Rac1 is a major actin regulator, our results support a model where the initial phase of long-term potentiation is driven by the cytoskeleton. ..
- Monine M, Haugh J. Signal transduction at point-blank range: analysis of a spatial coupling mechanism for pathway crosstalk. Biophys J. 2008;95:2172-82 pubmed publisher..We contend that this mechanism is a means by which signaling pathways are propagated and spatially coordinated for efficient crosstalk between them. ..
- Hong J, Doebele R, Lingen M, Quilliam L, Tang W, Rosner M. Anthrax edema toxin inhibits endothelial cell chemotaxis via Epac and Rap1. J Biol Chem. 2007;282:19781-7 pubmed..Similar to ET, activated Epac or Rap1 induces cytoskeletal changes and blocks chemotaxis in human endothelial cells. These results identify Epac and Rap1 as key regulators of signaling cascades leading to endothelial cell chemotaxis. ..
- Murayama K, Shirouzu M, Kawasaki Y, Kato Murayama M, Hanawa Suetsugu K, Sakamoto A, et al. Crystal structure of the rac activator, Asef, reveals its autoinhibitory mechanism. J Biol Chem. 2007;282:4238-42 pubmed..These results demonstrate that the blocking of the Rac-binding site by the SH3 domain is essential for Asef autoinhibition. This may be a common mechanism in other proteins that possess an SH3 domain adjacent to a DH-PH module. ..
- Calvo F, Crespo P. Structural and spatial determinants regulating TC21 activation by RasGRF family nucleotide exchange factors. Mol Biol Cell. 2009;20:4289-302 pubmed publisher..Finally, our data indicate that Cdc42-GDP can inhibit TC21 activation by RasGRF GEFs, demonstrating that Cdc42 negatively affects the functions of RasGRF GEFs irrespective of the GTPase being targeted. ..
- Arava Y, Seger R, Walker M. GRFbeta, a novel regulator of calcium signaling, is expressed in pancreatic beta cells and brain. J Biol Chem. 1999;274:24449-52 pubmed..The results suggest that GRF1 plays a role in mediating calcium-dependent signal transduction in beta cells and that GRFbeta represents a novel dominant negative modulator of Ras signaling. ..
- Zenker M, Horn D, Wieczorek D, Allanson J, Pauli S, van der Burgt I, et al. SOS1 is the second most common Noonan gene but plays no major role in cardio-facio-cutaneous syndrome. J Med Genet. 2007;44:651-6 pubmed..Mutations of SOS1, the gene encoding a guanine nucleotide exchange factor for Ras, have been the most recent discoveries in patients with NS, but this gene has not been studied in patients with CFCS...
- Gotoh T, Tian X, Feig L. Prenylation of target GTPases contributes to signaling specificity of Ras-guanine nucleotide exchange factors. J Biol Chem. 2001;276:38029-35 pubmed..These results indicate that the specific lipid moiety attached to GTPases can contribute to signaling specificity of Ras-GEFs. ..
- Yang H, Cooley D, Legakis J, Ge Q, Andrade R, Mattingly R. Phosphorylation of the Ras-GRF1 exchange factor at Ser916/898 reveals activation of Ras signaling in the cerebral cortex. J Biol Chem. 2003;278:13278-85 pubmed..In the prefrontal cortex, there was striking phosphorylation of Ras-GRF1 in the dendritic tree, supporting a role for Ras activation and signal transduction in neurotransmission in this area. ..
- Golec D, Dower N, Stone J, Baldwin T. RasGRP1, but not RasGRP3, is required for efficient thymic ?-selection and ERK activation downstream of CXCR4. PLoS ONE. 2013;8:e53300 pubmed publisher..Our results demonstrate that RasGRP1 is an important regulator of proliferation and differentiation at the ?-selection checkpoint and functions downstream of CXCR4 to activate the Ras/MAPK pathway. ..
- Oshita H, Nishino R, Takano A, Fujitomo T, Aragaki M, Kato T, et al. RASEF is a novel diagnostic biomarker and a therapeutic target for lung cancer. Mol Cancer Res. 2013;11:937-51 pubmed publisher..RASEF may play an important role in lung carcinogenesis and could serve as a vaiable prognostic biomarker and target for the development of new molecular therapies. ..
- Geyer M, Wilde C, Selzer J, Aktories K, Kalbitzer H. Glucosylation of Ras by Clostridium sordellii lethal toxin: consequences for effector loop conformations observed by NMR spectroscopy. Biochemistry. 2003;42:11951-9 pubmed..Inhibition of the glucosylation reaction by 1,5-gluconolactone suggests a stereospecific reaction mechanism with a glucosyl oxonium ion transition state for the enzymatic activity of LT. ..
- Rao Y, Bian C, Yuan C, Li Y, Chen L, Ye X, et al. An open conformation of switch I revealed by Sar1-GDP crystal structure at low Mg2+. Biochem Biophys Res Commun. 2006;348:908-15 pubmed..Furthermore, we propose a mechanism for COPII assembly and disassembly in which dimerization of Sar1 plays an important role. ..