Brefeldin A-inhibited guanine nucleotide-exchange protein 3 (BIG3) has been identified recently as a novel regulator of estrogen signalling in breast cancer cells. Despite being a potential target for new breast cancer treatment, its amino acid sequence suggests no association with any well-characterized protein family and provides little clues as to its molecular function. In this paper, we predicted the structure, function and interactions of BIG3 using a range of bioinformatic tools. Homology search results showed that BIG3 had distinct features from its paralogues, BIG1 and BIG2, with a unique region between the two shared domains, Sec7 and DUF1981. Although BIG3 contains Sec7 domain, the lack of the conserved motif and the critical glutamate residue suggested no potential guaninyl-exchange factor (GEF) activity. Fold recognition tools predicted BIG3 to adopt an α-helical repeat structure similar to that of the armadillo (ARM) family. Using state-of-the-art methods, we predicted interaction sites
Arfgef1 (untagged) - Mouse ADP-ribosylation factor guanine nucleotide-exchange factor 1(brefeldin A-inhibited) (Arfgef1), (10ug), 10 µg.
FUNCTION: Guanine nucleotide-exchange factor (GEF) required for the formation or budding of transport vesicles from the ER. This function involves the cytoplasmic domain of the protein, which is thought to interact with the small GTP-binding protein SAR1. Required for autophagy. MISCELLANEOUS: In the process of transport, SEC12 itself may migrate to the Golgi apparatus and function in subsequent transport events. MISCELLANEOUS: Present with 6160 molecules/cell in log phase SD medium ...
BioAssay record AID 720707 submitted by NCGC: qHTS for Agonist of cAMP-regulated guanine nucleotide exchange factor 3 (EPAC1): primary screen.
Members of the Rho family of GTP‐binding proteins function as molecular switches in biological response pathways that result in changes in the actin cytoskeletal architecture, the stimulation of cell cycle progression and gene transcription, and the regulation of intracellular trafficking activities (Van Aelst and DSouza‐Schorey, 1997; Hall, 1998; Bar‐Sagi and Hall, 2000; Erickson and Cerione, 2001). Three classes of proteins, GTPase‐activating proteins (GAPs), guanine nucleotide dissociation inhibitors (GDIs), and guanine nucleotide exchange factors (GEFs), regulate the cycling of these GTP‐binding proteins between their GDP‐bound and GTP‐bound states (Boguski and McCormick, 1993). Rho family proteins, such as Cdc42 and Rac, are activated by a number of upstream stimuli, as mediated by members of the Dbl (diffuse B‐cell lymphoma) family of GEFs (Whitehead et al, 1997; Hoffman and Cerione, 2002). One subgroup of the Dbl family, the Cool/Pix proteins (Cool for cloned‐out of ...
The Dbl family of guanine nucleotide exchange factors are multifunctional molecules that transduce diverse intracellular signals leading to the activation of Rho GTPases. The tandem Dbl-homology and pleckstrin-homology domains shared by all members of this family represent the structural module resp …
TY - JOUR. T1 - Identification and characterization of a new family of guanine nucleotide exchange factors for the Ras-related GTPase Ral. AU - Rebhun, John F.. AU - Chen, Hongsheng. AU - Quilliam, Lawrence A.. PY - 2000/5/5. Y1 - 2000/5/5. N2 - Guanine nucleotide exchange factors (GEFs) are responsible for coupling cell surface receptors to Ras protein activation. Here we describe the characterization of a novel family of differentially expressed GEFs, identified by database sequence homology searching. These molecules share the core catalytic domain of other Ras family GEFs but lack the catalytic non- conserved (conserved non-catalytic/Ras exchange motif/structurally conserved region 0) domain that is believed to contribute to Sos1 integrity. In vitro binding and in vivo nucleotide exchange assays indicate that these GEFs specifically catalyze the GTP loading of the Ral GTPase when overexpressed in 293T cells. A central proline-rich motif associated with the Src homology (SH)2/SH3-containing ...
We recently reported that brefeldin A-inhibited guanine nucleotide-exchange proteins 3 (BIG3) binds Prohibitin 2 (PHB2) in cytoplasm, thereby leading to a reduction of function of the PHB2 growth suppressor in the nuclei of breasts tumor cells. PHB2 nuclear transfer may offer restorative strategies for managing Elizabeth2/Emergency room signs in breasts tumor cells. Introduction Prohibitin 1 and 2 (PHB and buy 808118-40-3 PHB2) proteins are highly conserved in eukaryotic cells and exhibit diverse subcellular localization with different functions [1C3]. These molecules are primarily observed in inner mitochondrial membranes via their buy 808118-40-3 N-terminal transmembrane domain but are also present in several other localizations such as the cytosol, endoplasmic reticulum, nucleus, and plasma membrane [1]. Both proteins form hetero-oligomeric ring structures in the inner mitochondrial membrane and function as chaperones buy 808118-40-3 that maintain mitochondrial integrity and stabilize ...
casSAR Dugability of A3NLC8 | bopE | Guanine nucleotide exchange factor BopE - Also known as BOPE_BURP6, bopE. Activator for both CDC42 and RAC1 by directly interacting with these Rho GTPases and acting as a guanine nucleotide exchange factor (GEF). This activation results in actin cytoskeleton rearrangements and stimulates membrane ruffling, thus promoting bacterial entry into non-phagocytic cells (By similarity). Monomer. Interacts with human CDC42 (By similarity).
TY - JOUR. T1 - REI-1 Is a Guanine Nucleotide Exchange Factor Regulating RAB-11 Localization and Function in C. elegans Embryos. AU - Sakaguchi, Aisa. AU - Sato, Miyuki. AU - Sato, Katsuya. AU - Gengyo-Ando, Keiko. AU - Yorimitsu, Tomohiro. AU - Nakai, Junichi. AU - Hara, Taichi. AU - Sato, Ken. AU - Sato, Ken. PY - 2015/10/26. Y1 - 2015/10/26. N2 - The small GTPase Rab11 dynamically changes its location to regulate various cellular processes such as endocytic recycling, secretion, and cytokinesis. However, our knowledge of its upstream regulators is still limited. Here, we identify the RAB-11-interacting protein-1 (REI-1) as a unique family of guanine nucleotide exchange factors (GEFs) for RAB-11 in Caenorhabditis elegans. Although REI-1 and its human homolog SH3-binding protein 5 do not contain any known Rab-GEF domains, they exhibited strong GEF activity toward Rab11 in vitro. In C. elegans, REI-1 is expressed in the germline and co-localizes with RAB-11 on the late-Golgi membranes. The loss ...
Guanine nucleotide exchange factor that catalyzes guanine nucleotide exchange on RHOA and CDC42, and thereby contributes to the regulation of RHOA and CDC42 signaling pathways. Seems to lack activity with RAC1. Becomes activated and highly tumorigenic by truncation of the N-terminus.
We investigated how the type III secretion system WxxxE effectors EspM2 of enterohaemorrhagic Escherichia coli, which triggers stress fibre formation, and SifA of Salmonella enterica serovar Typhimurium, which is involved in intracellular survival, modulate Rho GTPases. We identified a direct interaction between EspM2 or SifA and nucleotide-free RhoA. Nuclear Magnetic Resonance Spectroscopy revealed that EspM2 has a similar fold to SifA and the guanine nucleotide exchange factor (GEF) effector SopE. EspM2 induced nucleotide exchange in RhoA but not in Rac1 or H-Ras, while SifA induced nucleotide exchange in none of them. Mutating W70 of the WxxxE motif or L118 and I127 residues, which surround the catalytic loop, affected the stability of EspM2. Substitution of Q124, located within the catalytic loop of EspM2, with alanine, greatly attenuated the RhoA GEF activity in vitro and the ability of EspM2 to induce stress fibres upon ectopic expression. These results suggest that binding of SifA to RhoA ...
Development of metastasis in breast cancer is a multi-step process comprising changes in cytoskeletal structure and gene expression of tumour cells leading to changes in cell adhesion and motility. The Rho GTPase proteins, which function as guanine nucleotide regulated binary switches, govern a variety of cellular processes including cell motility and migration, changes in cell adhesion as well as actin cytoskeletal reorganisation and gene expression/transcription. One group of activators which regulate the Rho-GTPases is the guanine nucleotide exchange factors (GEFs), and this study looked at three such GEFs, Trio, Vav1 and TIAM-1. The purpose of this study was to investigate the expression of these GEFs, in human breast cancer and assess the affect on clinical outcome. Specimens of fresh, frozen breast tumour tissue (n = 113) and normal background tissue (n = 30) were processed for quantitative PCR analysis. The expression and levels of expression of Trio, Vav1 and TIAM-1 were analysed using RT-PCR
ADP ribosylation factor 6 (Arf6) is a small GTPase that regulates dendritic differentiation possibly through the organization of actin cytoskeleton and membrane traffic. Here, we characterized IQ-ArfGEF/BRAG1, a guanine nucleotide exchange factor (GEF) for Arf6, in the mouse brain. In vivo Arf pull …
Domain combinations containing the Calponin-homology domain, CH-domain superfamily in Drosophila persimilis 1.3. Domain architectures illustrate each occurrence of the Calponin-homology domain, CH-domain superfamily.
Wiskott-Aldrich syndrome (WAS) is associated with mutations in the WAS protein (WASp), which plays a critical role in the initiation of T cell receptor-driven (TCR-driven) actin polymerization. The clinical phenotype of WAS includes susceptibility to infection, allergy, autoimmunity, and malignancy and overlaps with the symptoms of dedicator of cytokinesis 8 (DOCK8) deficiency, suggesting that the 2 syndromes share common pathogenic mechanisms. Here, we demonstrated that the WASp-interacting protein (WIP) bridges DOCK8 to WASp and actin in T cells. We determined that the guanine nucleotide exchange factor activity of DOCK8 is essential for the integrity of the subcortical actin cytoskeleton as well as for TCR-driven WASp activation, F-actin assembly, immune synapse formation, actin foci formation, mechanotransduction, T cell transendothelial migration, and homing to lymph nodes, all of which also depend on WASp. These results indicate that DOCK8 and WASp are in the same signaling pathway that ...
RAB-10/Rab10 is a master regulator of endocytic recycling in epithelial cells. To better understand the regulation of RAB-10 activity, we sought to identify RAB-10(GDP)-interacting proteins. One novel RAB-10(GDP)-binding partner that we identified, LET-413, is the Caenorhabditis elegans homologue of Scrib/Erbin. Here, we focus on the mechanistic role of LET-413 in the regulation of RAB-10 within the C. elegans intestine. We show that LET-413 is a RAB-5 effector and colocalizes with RAB-10 on endosomes, and the overlap of LET-413 with RAB-10 is RAB-5 dependent. Notably, LET-413 enhances the interaction of DENN-4 with RAB-10(GDP) and promotes DENN-4 guanine nucleotide exchange factor activity toward RAB-10. Loss of LET-413 leads to cytosolic dispersion of the RAB-10 effectors TBC-2 and CNT-1. Finally, we demonstrate that the loss of RAB-10 or LET-413 results in abnormal overextensions of lateral membrane. Hence, our studies indicate that LET-413 is required for DENN-4-mediated RAB-10 activation, ...
Colomer V، Engelender S، Sharp AH، Duan K، Cooper JK، Lanahan A، Lyford G، Worley P، Ross CA (September 1997). "Huntingtin-associated protein 1 (HAP1) binds to a Trio-like polypeptide, with a rac1 guanine nucleotide exchange factor domain". Hum. Mol. Genet. 6 (9): 1519-25. PMID 9285789. doi:10.1093/hmg/6.9.1519. .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output .citation q{quotes:""""""""}.mw-parser-output .citation .cs1-lock-free a{background:url("//upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .citation .cs1-lock-limited a,.mw-parser-output .citation .cs1-lock-registration a{background:url("//upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .citation .cs1-lock-subscription ...
Abstract Chemotaxis, or directional movement toward extracellular chemical gradients, is an important property of cells that is mediated through G-protein-coupled receptors (GPCRs). Although many chemotaxis pathways downstream of Gβγ have been identified, few Gα effectors are known. Gα effectors are of particular importance because they allow the cell to distinguish signals downstream of distinct chemoattractant GPCRs. Here we identify GflB, a Gα2 binding partner that directly couples the Dictyostelium cyclic AMP GPCR to Rap1. GflB localizes to the leading edge and functions as a Gα-stimulated, Rap1-specific guanine nucleotide exchange factor required to balance Ras and Rap signaling. The kinetics of GflB translocation are fine-tuned by GSK-3 phosphorylation. Cells lacking GflB display impaired Rap1/Ras signaling and actin and myosin dynamics, resulting in defective chemotaxis. Our observations demonstrate that GflB is an essential upstream regulator of chemoattractant-mediated cell ...
Capacitation encompasses the molecular changes sperm undergo to fertilize an oocyte, some of which are postulated to occur via a cAMP-PRKACA (protein kinase A)-mediated pathway. Due to the recent discovery of cAMP-activated guanine nucleotide exchange factors RAPGEF3 and RAPGEF4, we sought to investigate the separate roles of PRKACA and RAPGEF3/RAPGEF4 in modulating capacitation and acrosomal exocytosis. Indirect immunofluorescence localized RAPGEF3 to the acrosome and subacrosomal ring and RAPGEF4 to the midpiece in equine sperm. Addition of the RAPGEF3/RAPGEF4-specific cAMP analogue 8-(p-chlorophenylthio)-2-O-methyladenosine-3,5-cyclic monophosphate (8pCPT) to sperm incubated under both noncapacitating and capacitating conditions had no effect on protein tyrosine phosphorylation, thus supporting a PRKACA-mediated event. Conversely, activation of RAPGEF3/RAPGEF4 with 8pCPT induced acrosomal exocytosis in capacitated equine sperm at rates (34%) similar (P > 0.05) to those obtained in ...
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes a member of the Rho-guanine nucleotide exchange factor (Rho-GEF) family. These proteins regulate Rho GTPases by catalyzing the exchange of GDP for GTP. The encoded protein specifically activates RhoG and plays a role in the promotion of macropinocytosis. Underexpression of the encoded protein may be a predictive marker of chemoresistant disease. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Oct 2011 ...
In mammalian cells vesicle transport is an important process, many diseases are caused by defects of trafficking. Key elements for organelle trafficking are Rab proteins which regulate this system. Rabs are GTPases and belong to the Ras superfamily proteins. Rab27a is one of the main actors of this process, it promotes the recruitment of secretory vesicles at the release site, the plasma membrane, by its role of interconnection between the vesicle and the motor protein myosin V. Dysfunction leads to disease such as Griscelli syndrome. Rab27a is a molecular switch, in the active state is able to bind effectors. The switching from the GDP-bound to the GTP-bound is catalysed by Rab3GEP. Furthermore, to function properly Rab27a has to be targeted to the organelle membrane, this function has been attributed to the guanine exchange factor as well. Rab3GEP contains a DENN domain (differentially expressed in normal versus neoplastic) at the N-terminus and a death domain at the C-terminus. Rab3GEP ...
Rab1 is a small GTPase regulating vesicular traffic between early compartments of the secretory pathway. To explore the role of rab1 we have analyzed the function of a mutant (rab1a[S25N]) containing a substitution which perturbs Mg2+ coordination and reduces the affinity for GTP, resulting in a form which is likely to be restricted to the GDP-bound state. The rab1a(S25N) mutant led to a marked reduction in protein export from the ER in vivo and in vitro, indicating that a guanine nucleotide exchange protein (GEP) is critical for the recruitment of rab1 during vesicle budding. The mutant protein required posttranslational isoprenylation for inhibition and behaved as a competitive inhibitor of wild-type rab1 function. Both rab1a and rab1b (92% identity) were able to antagonize the inhibitory activity of the rab1a(S25N) mutant, suggesting that these two isoforms are functionally interchangeable. The rab1 mutant also inhibited transport between Golgi compartments and resulted in an apparent loss of ...
... G protein-mediated signaling exhibiting another role during regulation of cell division. regulates Ric-8B expression negatively. During osteoblast differentiation Ric-8B gene repression can be accompanied by adjustments in nucleosome positioning in the proximal Ric-8B gene promoter and decreased option of regulatory sequences. Intro Guanine nucleotide exchange elements (GEFs) are essential regulators from the function of heterotrimeric G proteins complexes in the plasma membrane in eukaryotic cells (35). CCG-63802 GEFs promote the alternative of the GDP destined to the Gα subunit by GTP therefore leading to the type of this proteins and therefore improving the G-mediated signaling cascades (35). Ric-8 was originally identified in as a gene that confers resistance to Fgfr1 inhibitors of cholinesterase in a mutant strain (RIC-8 [resistance to inhibitors CCG-63802 of cholinesterase 8]) (22 23 Using Gα proteins as bait during ...
We have described the function of the Sec7 domain protein Garz in epithelial tube development during Drosophila embryogenesis. We show that garz is essential for tracheal tube expansion and for epithelial protein secretion. Garz protein localizes to the Golgi and is required for normal Golgi morphology and for correct localization of COPI components. Garz is a member of the conserved Sec7-domain-containing family of large ARF-GEF proteins, which are involved in membrane-budding events at different intracellular compartments. Two families of large ARF-GEFs are known, the BIG and the GBF1 families. BIG1 and BIG2 localize to the TGN (BIG1 and BIG2) (Zhao et al., 2002) or recycling endosomes (BIG2) (Shin et al., 2004), where they facilitate recruitment of clathrin coat proteins. By contrast, GBF1 acts at the cis-Golgi membrane, where it initiates COPI vesicle formation by activating a class I ARF protein (Kawamoto et al., 2002; Garcia-Mata et al., 2003). Six different Sec7 domain proteins are ...
Mimicry grasps reality in translation termination. A posttermination ribosomal complex is the guanine nucleotide exchange factor for peptide release factor RF3
This entry represents the ELMO (EnguLfment and Cell MOtility) domain, which is found in a number of eukaryotic proteins involved in the cytoskeletal rearrangements required for phagocytosis of apoptotic cells and cell motility, including CED-12, ELMO-1 and ELMO-2. ELMO-1 and ELMO-2 are components of signalling pathways that regulate phagocytosis and cell migration and are mammalian orthologues of the Caenorhabditis elegans gene, ced-12 that is required for the engulfment of dying cells and cell migration. ELMO-1/2 act in association with DOCK1 and CRK. ELMO-1/2 interact with the SH3-domain of DOCK1 via an SH3-binding site to enhance the guanine nucleotide exchange factor (GEF) activity of DOCK1. ELMO-1/2 could be part of a complex with DOCK1 and Rac1 that could be required to activate Rac Rho small GTPases. Regulatory GTPases in the Ras superfamily employ a cycle of alternating GTP binding and hydrolysis, controlled by guanine nucleotide exchange factors and GTPase-activating proteins (GAPs), as ...
ARHGEF18 antibody (Rho/Rac guanine nucleotide exchange factor (GEF) 18) for ICC/IF, WB. Anti-ARHGEF18 pAb (GTX102223) is tested in Human samples. 100% Ab-Assurance.
Rho family GTPases, members of the Ras superfamily of G proteins, govern multiple cellular processes, including proliferation, transformation, cell motility, and apoptosis. Numerous studies reveal that the Rho GTPases Rac and Cdc42 can either promote or inhibit apoptosis, depending on the cell type and apoptotic stimulus examined. For example, in fibroblasts and some hematopoietic cells, constitutively active Rac protects cells from apoptosis induced by Ras or factor withdrawal (1, 2, 3) . In contrast, activated Rac and Cdc42 can induce apoptosis in Jurkat T lymphocytes, thymocytes, peripheral T cells, and neuronal cell lines (4, 5, 6, 7, 8, 9, 10) . Most forms of apoptosis require the activation of a family of proteases termed caspases (11) . A growing number of cellular proteins have been identified as caspase substrates, and in some cases, cleavage has been shown to modulate their biochemical activity, contributing to various aspects of the apoptotic program. For example, two caspase ...
The guanine nucleotide exchange factor (GEF) Vav1 is essential for transducing T cell antigen receptor (TCR) signals and therefore plays a critical role in the development and activation of T cells. It has been presumed that the GEF activity of Vav1 is important for its function; however, there has been no direct demonstration of this. Here, we generated mice expressing enzymatically inactive, but normally folded, Vav1 protein. Analysis of these mice showed that the GEF activity of Vav1 was necessary for the selection of thymocytes and for the optimal activation of T cells, including signal transduction to Rac1, Akt, and integrins. In contrast, the GEF activity of Vav1 was not required for TCR-induced calcium flux, activation of extracellular signal-regulated kinase and protein kinase D1, and cell polarization. Thus, in T cells, the GEF activity of Vav1 is essential for some, but not all, of its functions.. ...
View mouse Rabgef1 Chr5:130171798-130214342 with: phenotypes, sequences, polymorphisms, proteins, references, function, expression
Stimulates the exchange of guanyl nucleotides associated with the GTPase ARF. Under normal cellular physiological conditions, the concentration of GTP is higher than that of GDP, favoring the replacement of GDP by GTP in association with the GTPase ...
The Gene Ontology (GO) project is a collaborative effort to address the need for consistent descriptions of gene products across databases. You can use this browser to view terms, definitions, and term relationships in a hierarchical display. Links to summary annotated gene data at MGI are provided in Term Detail reports.
Vav and Dbl are members of a novel class of oncogene proteins that share significant sequence identity in a approximately 250-amino-acid domain, designated the Dbl homology domain. Although Dbl functions as a guanine nucleotide exchange factor (GEF) and activator of Rho family proteins, recent evidence has demonstrated that Vav functions as a GEF for Ras proteins. Thus, transformation by Vav and Dbl may be a consequence of constitutive activation of Ras and Rho proteins, respectively. To address this possibility, we have compared the transforming activities of Vav and Dbl with that of the Ras GEF, GRF/CDC25. As expected, GRF-transformed cells exhibited the same reduction in actin stress fibers and focal adhesions as Ras-transformed cells. In contrast, Vav- and Dbl-transformed cells showed the same well-developed stress fibers and focal adhesions observed in normal or RhoA(63L)-transformed NIH 3T3 cells. Furthermore, neither Vav- or Dbl-transformed cells exhibited the elevated levels of Ras-GTP ...
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes a member of the dedicator of cytokinesis protein family. Members of this family are guanosine nucleotide exchange factors for Rho GTPases and defined by the presence of conserved DOCK-homology regions. The encoded protein belongs to the D (or Zizimin) subfamily of DOCK proteins, which also contain an N-terminal pleckstrin homology domain. Alternatively spliced transcript variants that encode different isoforms have been described. [provided by RefSeq, Mar 2014 ...
The strict spatio-temporal control of Rho GTPases is critical for many cellular functions, including cell motility, contractility, and growth. In this regard, the prototypical Rho family GTPases, Rho, Rac, and Cdc42 regulate the activity of each other by a still poorly understood mechanism. Indeed, we found that constitutively active forms of Rac inhibit stress fiber formation and Rho stimulation by thrombin. Surprisingly, a mutant of Rac that is unable to activate Pak1 failed to inhibit thrombin signaling to Rho. To explore the underlying mechanism, we investigated whether Pak1 could regulate guanine nucleotide exchange factors (GEFs) for Rho. We found that Pak1 associates with P115-RhoGEF but not with PDZ-RhoGEF or LARG, and knock down experiments revealed that P115-RhoGEF plays a major role in signaling from thrombin receptors to Rho in HEK293T cells. Pak1 binds the DH-PH domain of P115-RhoGEF, thus suggesting a mechanism by which Rac stimulation of Pak1 may disrupt receptor-dependent Rho signaling.
This gene is a member of the dedicator of cytokinesis (DOCK) family and encodes a protein with a DHR-1 (CZH-1) domain, a DHR-2 (CZH-2) domain and an SH3 domain. This membrane-associated, cytoplasmic protein functions as a guanine nucleotide exchange factor and is involved in regulation of adherens junctions between cells. Mutations in this gene have been associated with ovarian, prostate, glioma, and colorectal cancers. Alternatively spliced variants which encode different protein isoforms have been described, but only one has been fully characterized.
This gene is a member of the dedicator of cytokinesis (DOCK) family and encodes a protein with a DHR-1 (CZH-1) domain, a DHR-2 (CZH-2) domain and an SH3 domain. This membrane-associated, cytoplasmic protein functions as a guanine nucleotide exchange factor and is involved in regulation of adherens junctions between cells. Mutations in this gene have been associated with ovarian, prostate, glioma, and colorectal cancers. Alternatively spliced variants which encode different protein isoforms have been described, but only one has been fully characterized. [provided by RefSeq, Jul 2008 ...
The protein encoded by this gene acts as a guanine nucleotide exchange factor for the RHO family of small GTP-binding proteins (RACs). It has been shown to bind to and activate RAC1 by exchanging bound GDP for free GTP. The encoded protein, which is found mainly in the cytoplasm, is activated by phosphatidylinositol-3,4,5-trisphosphate and the beta-gamma subunits of heterotrimeric G proteins. [provided by RefSeq, Jul 2008 ...
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Objectives: The Rho subfamily of small GTPases, including RhoA, Rac1, and Cdc42, regulates diverse cellular functions, including polarity and migration. Our prior studies established an essential role for Cdc42 in vascular network assembly, demonstrating that the genetic inactivation of Cdc42 yields defective vascular morphogenesis due to impaired migration of endothelial precursor cells. We have further shown that protein kinase Ciota and glycogen synthase kinase-3 Beta are downstream effectors of Cdc42 involved in mediating vascular network assembly. The objective of this study was to elucidate the guanine nucleotide exchange factors (GEFs) that activate Cdc42; specifically, we investigated the role of Zizimin1 and its effects on Cdc42 and vasculogenesis.. Methods: We performed affinity pulldown assays using a nucleotide-free Cdc42 G15A mutant that specifically binds to Cdc42 GEFs. Mass spectrometric analysis identified Zizimin1 as a candidate Cdc42 GEF.. Results: During vasculogenesis in ...
J Cell Biol. 2008 183:499-511.. 2. Structural analysis of Rme-6, a rab5GEF that integrates endocytosis and signalling. Co-Supervisor: Professor Per Bullough. The ras family of small molecular weight GTPases act as molecular switches. In their active GTP conformation, they interact with a variety of effectors to perform a range of physiological functions. Conversion to the GTP conformation is mediated by guanine nucleotide exchange factors (GEFs) while GTPases are inactivated by GTP hydrolysis, facilitated by GTPase activating proteins (GAPs). Ras is the founding member of this family and has many roles in intracellular signalling and mutations in ras can result in cancer.. The rab family of small GTPases regulates many aspects of membrane trafficking and rab5 is considered to be a master regulator of the early endocytic pathway (Stenmark, 2009). Rme-6 is a multidomain protein containing an N-terminal rasGAP domain and a C-terminal rab5 GEF domain connected by a flexible linker. We have evidence ...
Fig. 2 Inhibition of Gαi1 bearing an engineered FR-binding site.. (A) Amino acid residues in Gαi1 identical to or diverged from the FR-binding site in Gαq are indicated in blue and red, respectively. An FR-binding site was engineered in Gαi1 by introducing the eight indicated amino acid substitutions so as to match the corresponding residues of Gαq, thereby producing a chimeric Gα subunit termed Gi/q. (B) Effect of FR on guanine nucleotide exchange by Gαi/q in vitro. Nucleotide exchange was assayed by measuring increase in BODIPY-GTPγS fluorescence upon binding to the indicated purified His-tagged Gα subunits in the absence or presence of the indicated concentrations of FR. Gi/q(R54K) corresponds to a Gαq mutant that is less sensitive to inhibition by FR. Nucleotide exchange rates (kobs) of Gαi/q and Gαi/q(R54K) in the absence of FR were 0.24 and 0.12 min−1, respectively. Data are means ± SEM from three independent experiments. (C) Effect of FR on agonist-evoked signaling mediated ...
cytoplasm, guanyl-nucleotide exchange factor complex, perinuclear region of cytoplasm, GTPase activator activity, kinase binding, Ras GTPase binding, Ras guanyl-nucleotide exchange factor activity, Ras protein signal transduction, regulation of GTPase activity
TY - JOUR. T1 - Still life, a protein in synaptic terminals of Drosophila homologous to GDP-GTP exchangers. AU - Sone, Masaki. AU - Hoshino, Mikio. AU - Suzuki, Emiko. AU - Kuroda, Shinya. AU - Kaibuchi, Kozo. AU - Nakagoshi, Hideki. AU - Saigo, Kaoru. AU - Nabeshima, Yo Ichi. AU - Hama, Chihiro. PY - 1997/1/24. Y1 - 1997/1/24. N2 - The morphology of axon terminals changes with differentiation into mature synapses. A molecule that might regulate this process was identified by a screen of Drosophila mutants for abnormal motor activities. The still life (sif) gene encodes a protein homologous to guanine nucleotide exchange factors, which convert Rho-like guanosine triphosphatases (GTPases) from a guanosine diphosphate-bound inactive state to a guanosine triphosphate-bound active state. The SIF proteins are found adjacent to the plasma membrane of synaptic terminals. Expression of a truncated SIF protein resulted in defects in neuronal morphology and induced membrane ruffling with altered actin ...
In biology, small GTPases are small (20-25 kDa) proteins that bind to guanosine triphosphate (GTP). This family of proteins is homologous to Ras GTPases and also called the Ras superfamily GTPases. Together with heterotrimeric G-proteins they constitute the G-proteins. They are all GTPases and share common features, but small GTPases have slightly different structures and mechanisms of action. A typical G-protein is active when bound to GTP and inactive when bound to GDP (i.e. when the GTP is hydrolyzed to GDP). The GDP can be then replaced by free GTP. Therefore, a G-protein can be switched on and off. GTP hydrolysis is accelerated by GTPase accelating proteins (GAPs), while GTP exchange is catalyzed by Guanine nucleotide exchange factors (GEFs). Activation of a GEF typically activates its cognate G-protein, while activation of a GAP results in inactivation of the cognate G-protein. Small GTPases regulate a wide variety of processes in the cell, including growth, cellular differentiation, cell ...
Deficiency in the guanine nucleotide exchange factor dedicator of cytokinesis 8 (DOCK8) causes a human immunodeficiency syndrome associated with recurrent sinopulmonary and viral infections. We have recently identified a DOCK8-deficient mouse strain, carrying an ethylnitrosourea-induced splice-site mutation that shows a failure to mature a humoral immune response due to the loss of germinal centre B cells. In this study, we turned to T-cell immunity to investigate further the human immunodeficiency syndrome and its association with decreased peripheral CD4(+) and CD8(+) T cells. Characterisation of the DOCK8-deficient mouse revealed T-cell lymphopenia, with increased T-cell turnover and decreased survival. Egress of mature CD4(+) thymocytes was reduced with increased migration of these cells to the chemokine CXCL12. However, despite the two-fold reduction in peripheral naïve T cells, the DOCK8-deficient mice generated a normal primary CD8(+) immune response and were able to survive acute influenza
Ect2 is a guanine nucleotide exchange factor (GEF) and activator of Rho family small GTPases. Ect2 regulates RhoA, Rac1, and Cdc42, thereby playing an important role in the control of cell proliferation, survival, and migration. Originally identified as an oncogene in vitro, the role of Ect2 in regulating migration makes it of particular interest in ovarian cancer, in which local invasion and ascites are prevalent. Notably, ECT2 is located on 3q26.1-3q26.2, the most frequent amplicon in ovarian cancer, and it has been found to be overexpressed at the mRNA level in ovarian tumors. We first explored the role of Ect2 in ovarian cancer by knocking it down using shRNA and assessing anchorage-independent growth and both random and directed migration in a panel of ovarian cancer cell lines. Our findings reveal that Ect2 expression is required for each of these functions. Interestingly, we found that Ect2 utilization of specific Rho GTPase substrates is highly context-dependent. In addition, to ...
The Ras proteins are GTPases that function as molecular switches for signaling pathways regulating cell proliferation, survival, growth, migration, differentiation or cytoskeletal dynamism. Ras proteins transduce signals from extracellular growth factors by cycling between inactive GDP-bound and active GTP-bound states. The exchange of GTP for GDP on RAS is regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Activated RAS (RAS-GTP) regulates multiple cellular functions through effectors including Raf, phosphatidylinositol 3-kinase (PI3K) and Ral guanine nucleotide-dissociation stimulator (RALGDS ...
Our results suggest that Ang II activates RhoA in cardiac myocytes. RhoA mediates Ang II-induced formation of nonstriated sarcomeric actin fibers (premyofibrils), which are distinct from stress fibers, in cardiac myocytes. Considering the existence of multiple downstream target molecules and the pleiotropic functions of Rho as reported in other cell types (References 30, 39, and 4030 39 40 ; see Reference 22 for review), RhoA may play an important role in remodeling processes of the heart caused by Ang II.. Since Rho is a member of the small GTP-binding proteins, activation of Rho could be shown by its increased binding of GTP. However, the guanine nucleotide binding assay or determination of the guanine nucleotide exchange activity for Rho has been technically difficult because the available antibody is not suitable for immunoprecipitating the native form of Rho41 in the presence of Mg2+ (authors unpublished data, 1997). Since Mg2+ is essential for preserving the guanine nucleotide binding of ...