Schultz et al. (1998) Proc. Natl. Acad. Sci. USA 95, 5857-5864
Letunic et al. (2012) Nucleic Acids Res , doi:10.1093/nar/gkr931

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RasGEF Guanine nucleotide exchange factor for Ras-like small GTPases

SMART accession number:	SM00147
Description:
Interpro abstract (IPR001895):	Ras proteins are membrane-associated molecular switches that bind GTP and GDP and slowly hydrolyze GTP to GDP [(PUBMED:1898771)]. The balance between the GTP bound (active) and GDP bound (inactive) states is regulated by the opposite action of proteins activating the GTPase activity and that of proteins which promote the loss of bound GDP and the uptake of fresh GTP [(PUBMED:8259209), (PUBMED:15335949)]. The latter proteins are known as guanine-nucleotide dissociation stimulators (GDSs) (or also as guanine-nucleotide releasing (or exchange) factors (GRFs)). Proteins that act as GDS can be classified into at least two families, on the basis of sequence similarities, the CDC24 family (see IPR001331) and the CDC25 family. The size of the proteins of the CDC25 family range from 309 residues (LTE1) to 1596 residues (sos). The sequence similarity shared by all these proteins is limited to a region of about 250 amino acids generally located in their C-terminal section (currently the only exceptions are sos and ralGDS where this domain makes up the central part of the protein). This domain has been shown, in CDC25 an SCD25, to be essential for the activity of these proteins.
GO process:	small GTPase mediated signal transduction (GO:0007264)
GO component:	intracellular (GO:0005622)
GO function:	guanyl-nucleotide exchange factor activity (GO:0005085)
Family alignment:	View or CHROMA formatCLUSTALW formatMSF formatFASTA formatPIR format

There are 1626 RasGEF domains in 1626 proteins in SMART's nrdb database.

Click on the following links for more information.

• Evolution (species in which this domain is found)

• Click on to expand nodes. To display all proteins with a RasGEF domain in a specific node, click on it.

  This tree shows only several representative species. The complete taxonomic breakdown of all proteins with RasGEF domain is also avaliable.

  Useful shortcuts: Expand all nodes or Collapse tree
  Go to specific node: Anopheles gambiae, Caenorhabditis elegans, Drosophila melanogaster, Homo sapiens, Mus musculus, Rattus norvegicus, Saccharomyces cerevisiae, Takifugu rubripes

• Cellular role (predicted cellular role)

• Cellular role: signalling
  Binding / catalysis: protein-binding, Ras-binding, guanine nucleotide exchange activity towards Ras

• Literature (relevant references for this domain)

• Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.

  • Nimnual AS, Yatsula BA, Bar-Sagi D
  • Coupling of Ras and Rac guanosine triphosphatases through the Ras exchanger Sos.
  • Science. 1998; 279: 560-3
  • Display abstract

  • The Son of Sevenless (Sos) proteins control receptor-mediated activation of Ras by catalyzing the exchange of guanosine diphosphate for guanosine triphosphate on Ras. The NH2-terminal region of Sos contains a Dbl homology (DH) domain in tandem with a pleckstrin homology (PH) domain. In COS-1 cells, the DH domain of Sos stimulated guanine nucleotide exchange on Rac but not Cdc42 in vitro and in vivo. The tandem DH-PH domain of Sos (DH-PH-Sos) was defective in Rac activation but regained Rac stimulating activity when it was coexpressed with activated Ras. Ras-mediated activation of DH-PH-Sos did not require activation of mitogen-activated protein kinase but it was dependent on activation of phosphoinositide 3-kinase. These results reveal a potential mechanism for coupling of Ras and Rac signaling pathways.

  • 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
  • Display abstract

  • Cell biology depends on the interactions of macromolecules, such as protein-DNA, protein-protein or protein-nucleotide interactions. GTP-binding proteins are no exception to the rule. They regulate cellular processes as diverse as protein biosynthesis and intracellular membrane trafficking. 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.

  • Byrne JL, Paterson HF, Marshall CJ
  • p21Ras activation by the guanine nucleotide exchange factor Sos, requires the Sos/Grb2 interaction and a second ligand-dependent signal involving the Sos N-terminus.
  • Oncogene. 1996; 13: 2055-65
  • Display abstract

  • It has been suggested that a key event in growth factor-induced p21Ras activation by the guanine nucleotide exchange factor Sos, is the recruitment of Sos to the plasma membrane by its interaction with the adaptor protein Grb2. However, other evidence argues that the sub cellular localisation of Sos is independent of Grb2, and that the Sos/Grb2 interaction can be dispensed with for p21Ras activation. To clarify the role of the Sos/Grb2 interaction in ligand-stimulated p21Ras activation, we have utilised the observation that overexpression of the Sos C-terminal domain can effectively inhibit p21Ras-dependent signalling in three different mammalian systems. We have shown that concurrent expression of Grb2, but not SH2 or SH3 domain mutants of Grb2, or the alternative adaptor protein Nck, can rescue this inhibitory effect of the C-terminus. This shows that the Grb2/Sos interaction is required to mediate growth factor-dependent activation of p21Ras, and requires the presence of intact SH2 and SH3 domains of Grb2. This approach was also used for a functional analysis of Sos which revealed that growth factor dependent signals are transmitted through both the N-terminal and C-terminal domains.

  • Quilliam LA, Khosravi-Far R, Huff SY, Der CJ
  • Guanine nucleotide exchange factors: activators of the Ras superfamily of proteins.
  • Bioessays. 1995; 17: 395-404
  • Display abstract

  • Ras proteins function as critical relay switches that regulate diverse signaling pathways between cell surface receptors and the nucleus. Over the past 2-3 years researchers have identified many components of these pathways that mediate Ras activation and effector function. Among these proteins are several guanine nucleotide exchange factors (GEFs), which are responsible for directly interacting with and activating Ras in response to extracellular stimuli. Analogous GEFs regulate Ras-related proteins that serve other diverse cellular functions. In particular, a growing family of proteins (Dbl homology proteins) has recently been identified, which may function as GEFs for the Rho family of Ras-related proteins. This review summarizes our current knowledge of the structure, biochemistry and biology of Ras and Rho family GEFs. Additionally, we describe mechanisms of GEF activation of Ras in signal transduction and address the potential that deregulated GEFs might contribute to malignant transformation through chronic Ras protein activation.

  • Boguski MS, McCormick F
  • Proteins regulating Ras and its relatives.
  • Nature. 1993; 366: 643-54
  • Display abstract

  • GTPases of the Ras superfamily regulate many aspects of cell growth, differentiation and action. Their functions depend on their ability to alternate between inactive and active forms, and on their cellular localization. Numerous proteins affecting the GTPase activity, nucleotide exchange rates and membrane localization of Ras superfamily members have now been identified. Many of these proteins are much larger and more complex than their targets, containing multiple domains capable of interacting with an intricate network of cellular enzymes and structures.

  • Li N et al.
  • Guanine-nucleotide-releasing factor hSos1 binds to Grb2 and links receptor tyrosine kinases to Ras signalling.
  • Nature. 1993; 363: 85-8
  • Display abstract

  • Many of the actions of receptor tyrosine kinases are mediated by the protein Ras, including the activation of various downstream serine/threonine kinases and the stimulation of growth and differentiation. The human protein Grb2 binds to ligand-activated growth factor receptors and downstream effector proteins through its Src-homology (SH) domains SH2 and SH3, respectively, and like its homologue from Caenorhabditis elegans, Sem-5, apparently forms part of a highly conserved pathway by which these receptors can control Ras activity. Here we show that the SH3 domains of Grb2 bind to the carboxy-terminal part of hSos1, the human homologue of the Drosophila guanine-nucleotide-releasing factor for Ras, which is essential for control of Ras activity by epidermal growth factor receptor and sevenless. Moreover, a synthetic 10-amino-acid peptide containing the sequence PPVPPR specifically blocks the interaction. These results indicate that the Grb2/hSos1 complex couples activated EGF receptor to Ras signalling.

  • Skolnik EY et al.
  • The function of GRB2 in linking the insulin receptor to Ras signaling pathways.
  • Science. 1993; 260: 1953-5
  • Display abstract

  • Insulin-induced activation of extracellular signal-regulated kinases [ERKs, also known as mitogen-activated protein (MAP) kinases] is mediated by Ras. Insulin activates Ras primarily by increasing the rate of guanine nucleotide-releasing activity. Here, we show that insulin-induced activation of ERKs was enhanced by stable overexpression of growth factor receptor-bound protein 2 (GRB2) but not by overexpression of GRB2 proteins with point mutations in the Src homology 2 and 3 domains. Moreover, a dominant negative form of Ras (with Ser17 substituted with Asn) blocked insulin-induced activation of ERKs in cells that overexpressed GRB2. GRB2 overexpression led to increased formation of a complex between the guanine nucleotide-releasing factor Sos (the product of the mammalian homolog of son of sevenless gene) and GRB2. In response to insulin stimulation, this complex bound to tyrosine-phosphorylated IRS-1 (insulin receptor substrate-1) and Shc. In contrast to the activated epidermal growth factor receptor that binds the GRB2-Sos complex directly, activation of the insulin receptor results in the interaction of GRB2-Sos with IRS-1 and Shc, thus linking the insulin receptor to Ras signaling pathways.

  • Shou C, Farnsworth CL, Neel BG, Feig LA
  • Molecular cloning of cDNAs encoding a guanine-nucleotide-releasing factor for Ras p21.
  • Nature. 1992; 358: 351-4
  • Display abstract

  • The stimulation of a variety of cell surface receptors promotes the accumulation of the active, GTP-bound form of Ras proteins in cells. This is a critical step in signal transduction because inhibition of Ras activation by anti-Ras antibodies or dominant inhibitory Ras mutants blocks many of the effects of these receptors on cellular function. To reach the active GTP-bound state, Ras proteins must first release bound GDP. This rate-limiting step in GTP binding is thought to be catalysed by a guanine-nucleotide-releasing factor (GRF). Here we report the cloning of complementary DNAs from a rat brain library that encode a approximately 140K GRF for Ras p21 (p140Ras-GRF). Its carboxy-terminal region is similar to that of CDC25, a GRF for Saccharomyces cerevisiae RAS. This portion of Ras-GRF accelerated the release of GDP from RasH and RasN p21 in vitro, but not from the related RalA, or CDC42Hs GTP-binding proteins. A region in the amino-terminal end of Ras-GRF is similar to both the human breakpoint cluster protein, Bcr, and the dbl oncogene product, a guanine-nucleotide-releasing factor for CDC42Hs. An understanding of Ras-GRF function will enhance our knowledge of the many signal transduction pathways mediated by Ras proteins.

  • Hart MJ, Eva A, Evans T, Aaronson SA, Cerione RA
  • Catalysis of guanine nucleotide exchange on the CDC42Hs protein by the dbl oncogene product.
  • Nature. 1991; 354: 311-4
  • Display abstract

  • THE superfamily of low molecular mass GTP-binding proteins, for which the ras proteins are prototypes, has been implicated in the regulation of diverse biological activities including protein trafficking, secretion, and cell growth and differentiation. One member of this family, CDC42Hs (originally referred to as Gp or G25K), seems to be the human homologue of the Saccharomyces cerevisiae cell-division-cycle protein, CDC42Sc. A second S. cerevisiae protein, CDC24, which is known from complementation studies to act with CDC42Sc to regulate the development of normal cell shape and the selection of nonrandom budding sites in yeast, contains a region with sequence similarity to the dbl oncogene product. Here we show that dbl specifically catalyses the dissociation of GDP from CDC42Hs and thereby qualifies as a highly selective guanine nucleotide exchange factor for the GTP-binding protein. Although guanine nucleotide exchange activities have been previously described for other members of the Ras-related GTP-binding protein family, this is the first demonstration, to our knowledge, of the involvement of a human oncogenic protein in catalysing exchange activity.

• Metabolism (metabolic pathways involving proteins which contain this domain)

• Click the image to view the interactive version of the map in iPath

  % proteins involved KEGG pathway ID Description 12.04 map04010 MAPK signaling pathway 5.47 map04510 Focal adhesion 5.47 map04910 Insulin signaling pathway 5.47 map05211 Renal cell carcinoma 5.25 map05210 Colorectal cancer 3.72 map04664 Fc epsilon RI signaling pathway 3.72 map05213 Endometrial cancer 3.72 map04912 GnRH signaling pathway 3.72 map04630 Jak-STAT signaling pathway 3.72 map05220 Chronic myeloid leukemia 3.72 map04320 Dorso-ventral axis formation 3.72 map05215 Prostate cancer 3.72 map04012 ErbB signaling pathway 3.72 map05214 Glioma 3.72 map04810 Regulation of actin cytoskeleton 3.72 map04540 Gap junction 3.72 map04660 T cell receptor signaling pathway 3.72 map05221 Acute myeloid leukemia 3.72 map05223 Non-small cell lung cancer 3.72 map04650 Natural killer cell mediated cytotoxicity 3.28 map04670 Leukocyte transendothelial migration 1.75 map04720 Long-term potentiation 1.53 map05212 Pancreatic cancer 1.09 map00562 Inositol phosphate metabolism 1.09 map04070 Phosphatidylinositol signaling system 1.09 map04020 Calcium signaling pathway 0.66 map04111 Cell cycle - yeast This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with RasGEF domain which could be assigned to a KEGG orthologous group, and not all proteins containing RasGEF domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.

• Structure (3D structures containing this domain)

• 3D Structures of RasGEF domains in PDB

  PDB code	Main view	Title
  1bkd		Complex of human h-ras with human sos-1
  1nvu		Structural evidence for feedback activation by rasgtp of the ras-specific nucleotide exchange factor sos
  1nvv		Structural evidence for feedback activation by rasgtp of the ras-specific nucleotide exchange factor sos
  1nvw		Structural evidence for feedback activation by rasgtp of the ras-specific nucleotide exchange factor sos
  1nvx		Structural evidence for feedback activation by rasgtp of the ras-specific nucleotide exchange factor sos
  1xd2		Crystal structure of a ternary ras:sos:ras*gdp complex
  1xd4		Crystal structure of the dh-ph-cat module of son of sevenless (sos)
  1xdv		Experimentally phased structure of human the son of sevenless protein at 4.1 ang.
  2byv		Structure of the camp responsive exchange factor epac2 in its auto-inhibited state
  2ii0		Crystal structure of catalytic domain of son of sevenless (rem-cdc25) in the absence of ras
  2ije		Crystal structure of the cdc25 domain of rasgrf1
  3cf6		Structure of epac2 in complex with cyclic-amp and rap

• Links (links to other resources describing this domain)

• PFAM	RasGEF
  INTERPRO	IPR001895
  PROSITE	GDS_CDC25

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