Disease relevance of ARHGEF2

• Herein, we show that the hematopoietic-specific GEF VAV1 is ectopically expressed in primary pancreatic adenocarcinomas due to demethylation of the gene promoter [1].
• Mutations in ALS2, carrying three putative guanine exchange factor (GEF) domains, are causative for a juvenile, autosomal recessive form of amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, and infantile-ascending hereditary spastic paralysis [2].
• For example, the Legionella protein RalF was shown previously to be a Dot/Icm substrate that functions as a guanine nucleotide exchange factor (GEF) for the Arf family of eukaryotic small GTP-binding proteins [3].
• We observed a marked increase in the expression of Vav3, a Rho GTPase guanine nucleotide exchange factor (GEF), during the progression of human prostate cancer LNCaP cells to the androgen-independent derivative, LNCaP-R1 [4].
• SopE2, a Salmonella guanine nucleotide exchange factor (GEF), is also involved in intestinal inflammation [5].

Psychiatry related information on ARHGEF2

• METHODS: Behavioral measures, including prepulse inhibition (PPI) and total locomotor activity, after amphetamine exposure were assessed at postnatal day 20 (P20) (prepuberty), P40 (puberty), P60 (postpuberty), and P80 (adulthood) in animals previously exposed to allopregnanolone (10 mg/kg) on P2 and P5 [6].

High impact information on ARHGEF2

• RhoA and hence to ROK through a mechanism involving association of GEF, RhoA, and ROK in multimolecular complexes at the lipid cell membrane [7].
• Here, we show that the catalytic core of the Rab GEF Rabex-5 has a tandem architecture consisting of a Vps9 domain stabilized by an indispensable helical bundle [8].
• RCC1 (regulator of chromosome condensation), a beta propeller chromatin-bound protein, is the guanine nucleotide exchange factor (GEF) for the nuclear GTP binding protein Ran [9].
• Based on the available structural and biochemical evidence, we present a unified scenario for the GEF mechanism where interaction of the P loop lysine with an acidic residue is a crucial element for the overall reaction [9].
• Free RF3 is in vivo stably bound to GDP, and ribosomes in complex with RF1 or RF2 act as guanine nucleotide exchange factors (GEF) [10].

Biological context of ARHGEF2

• Furthermore, drug-induced microtubule depolymerization induces changes in cell morphology and gene expression that are similar to the changes induced by the expression of active forms of GEF-H1 [11].
• The mRNA for P40 was 2.8 kilobases long and was expressed maximally in G1 cells in cell cycle [12].
• We show that phosphorylation of GEF-H1 at Ser(885) by PAK1 induces 14-3-3 binding to the exchange factor and relocation of 14-3-3 to microtubules [13].
• Here we have identified a new member of the Dbl family, GEF-H1, by screening a human HeLa cell cDNA library [14].
• The guanine nucleotide-exchange factor (GEF) Ect2 is essential for cytokinesis [15].

Anatomical context of ARHGEF2

• GEF-H1 mutants that are deficient in microtubule binding have higher activity levels than microtubule-bound forms [11].
• Overexpression of GEF-H1 in COS-7 cells results in induction of membrane ruffles [14].
• In this study, we provide evidence that the Rho family GEF, Vav-2, is present in cytotoxic lymphocytes, and becomes tyrosine phosphorylated after the cross-linking of activating receptors on cytotoxic lymphocytes and during the generation of cell-mediated killing [16].
• We report that the Rac1-GEF Tiam1 is present in dendrites and spines and is required for their development [17].
• Rapid induction of dendritic spine morphogenesis by trans-synaptic ephrinB-EphB receptor activation of the Rho-GEF kalirin [18].

Associations of ARHGEF2 with chemical compounds

• The chemical compound NSC23766 was identified by a structure-based virtual screening of compounds that fit into a surface groove of Rac1 known to be critical for GEF specification [19].
• Here we identify a region in the carboxyl terminus of GEF-H1 that is important for suppression of its guanine nucleotide exchange activity by microtubules [13].
• Moreover, we found GEFH1 associated with RhoB, and DN-GEFH1 or GEFH1's RNAi suppressed the LPS-mediated RhoB activation and MHCII surface expression [20].
• 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 [21].
• The GDP dissociation rates of the GTPases could be further stimulated by GEF upon removal of bound Mg(2+), indicating that the GEF-catalyzed nucleotide exchange involves a Mg(2+)-independent as well as a Mg(2+)-dependent mechanism [22].
• The mitotic kinases Aurora A/B and Cdk1/Cyclin B phosphorylate GEF-H1, thereby inhibiting GEF-H1 catalytic activity [23].

Physical interactions of ARHGEF2

• The Rac1-GEF Tiam1 couples the NMDA receptor to the activity-dependent development of dendritic arbors and spines [17].

Enzymatic interactions of ARHGEF2

• p21-activated kinase 1 phosphorylates and regulates 14-3-3 binding to GEF-H1, a microtubule-localized Rho exchange factor [13].
• In addition, Ras-GRF1 acts as a GEF for Rac when tyrosine-phosphorylated following G protein-coupled receptor stimulation [24].

Regulatory relationships of ARHGEF2

• In contrast, a similar mutant of the Rac GEF beta-PIX fails to inhibit ARNO-induced Rac activation or motility [25].
• Cingulin binding inhibits RhoA activation and signaling, suggesting that the increase in cingulin expression in confluent cells causes downregulation of RhoA by inhibiting GEF-H1/Lfc [26].
• We demonstrated that AKAP-Lbc Rho-GEF activity is stimulated by the alpha subunit of the heterotrimeric G protein G12 [27].
• Activation of endogenous Rac1 by expression of constitutively active Rac-guanine nucleotide exchange factor (GEF) derivatives was sufficient to induce high level NADPH oxidase activity in COS(phox) cells [28].

Other interactions of ARHGEF2

• Furthermore, we conclude that the catalytic activity of Epac1 is constrained by a direct interaction between GEF and high affinity cAMP binding domains in the absence of cAMP [29].
• G alpha 13 stimulates the guanine nucleotide exchange factors (GEFs) for Rho, such as p115Rho-GEF [30].
• The results suggest that GEF facilitates nucleotide exchange by destabilizing both bound nucleotide and Mg(2+), whereas RhoGAP utilizes the Mg(2+) cofactor to achieve high catalytic efficiency and specificity [22].
• The Tgat cDNA encoded a protein product consisting of the Rho-guanosine nucleotide exchange factor (GEF) domain of a multifunctional protein, TRIO, and a unique C-terminal 15-amino acid sequence, which were derived from the exons 38-46 of the Trio gene and a novel exon located downstream of its last exon (exon 58), respectively [31].
• C-terminally truncated MR-GEF, lacking the GEF catalytic domain, retained its ability to bind M-Ras-GTP, suggesting that the RA domain is important for this interaction [32].

Analytical, diagnostic and therapeutic context of ARHGEF2

• Immunofluorescence reveals that GEF-H1 colocalizes with microtubules through the carboxyl-terminal coiled-coil domain [14].
• Primary sequence analysis revealed that it has the appearance of a natural chimera between a myosin motor domain and a guanine nucleotide exchange factor (GEF) domain for Rho GTPases [33].
• Furthermore, reverse transcriptase-polymerase chain reaction and immunoreplica analysis indicate that ARNO, a member of the brefeldin A-insensitive ARF-GEF family, is expressed and predominantly localized in the cytosol and in the plasma membrane of chromaffin cells [34].
• ECG estimation of REF from a modified Palmeri's equation showed a better correlation with radionuclide REF than did GEF derived from the standard Palmeri's equation: anterior MI; r = 0.90 vs r = 0.82, inferior MI; r = 0.84 vs r = 0.69, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)[35]
• METHODS: The flop:flip ratio and expression levels of GluR1-4 from postnatal day 8 (P8) to P40 were calculated using quantitative real-time polymerase chain reaction (PCR) analysis and immunoblot analysis [36].

References