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Gene Review

ARHGEF5  -  Rho guanine nucleotide exchange factor...

Homo sapiens

Synonyms: Ephexin-3, GEF5, Guanine nucleotide regulatory protein TIM, Oncogene TIM, P60, ...
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Disease relevance of ARHGEF5

  • We report here the identification of five novel ARHGEF5/TIM alternative transcripts specifically expressed in breast tumors [1].
  • We anticipate that the activation of the ARHGEF5/TIM oncogene, possibly by the variant isoforms detected here, may play an important role in proliferative breast disease [1].
  • We compared the metabolic response of a methionine(Met)-dependent (P60) human glioma cell line with that of a Met-independent variant (P60H) when cultured in a homocysteine (Hcy) medium and exposed to N2O [2].
  • Here we report the first high-resolution crystal structure of ACMSD from Pseudomonas fluorescens which validates our previous predictions that this enzyme is a member of the metal-dependent amidohydrolase superfamily of the (beta/alpha)(8) TIM barrel fold [3].
  • P60-c-src suppresses apoptosis through inhibition of caspase 8 activation in hepatoma cells, but not in primary hepatocytes [4].

Psychiatry related information on ARHGEF5

  • 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 [5].
  • Depression of the P60-N75 complex was correlated with the pain-induced loss of proprioception of the foot, making it plausible that this cortical complex reflects neuronal processes leading to perception [6].

High impact information on ARHGEF5

  • These T cell subsets are primarily differentiated on the basis of the cytokines that they produce, however, we have identified a novel gene family called TIM (T cell, immunoglobulin, mucin domain-containing molecules), whose members are differentially expressed on Th1 and Th2 cells [7].
  • Genomic association of the TIM family and polymorphisms in both Tim-1 and Tim-3 in different immune-mediated diseases suggest that the family may have an important role in regulating immunity, both in terms of normal immune responses and in diseases like autoimmunity and asthma [7].
  • Because of its localization close to the common fragile site FRA7I, which has been shown to be responsible for an inverted duplication of the 7q34-q35 region in breast carcinoma cells, we examined the expression of the ARHGEF5/TIM oncogene in normal and tumoral breast tissue [1].
  • Moreover, we demonstrate that the expression of recombinant ARHGEF5/TIM protein in transfected COS-7 and NIH-3T3 cells generated a loss of actin stress fibers and the formation of membrane ruffles and filopodia [1].
  • This activity requires TIM-1 tyrosine phosphorylation [8].

Chemical compound and disease context of ARHGEF5


Biological context of ARHGEF5


Anatomical context of ARHGEF5

  • This cohort of early generated cells, many of which become postmitotic on embryonic day (E) 14.5, differentiates into a wide range of mature OB interneurons by postnatal day (P) 21, and a substantial number remains in the OB at P60 [14].
  • Further metabolic differences were induced by N2O exposure, which markedly reduced Met-synthase activity in cell-free extracts in both cell lines and completely blocked intact-cell Hcy remethylation in P60, whereas Hcy remethylation was only partly inhibited in P60H cells cultured in Met medium [2].
  • This pattern persisted at P60: eight genes were more robustly expressed in the left hippocampus, and the remaining five showed no hemispheric preference [15].
  • The initial corticothalamic projection, detected by retrograde transport of WGA-HRP from the thalamus, occurred at P60 from layer 5 cells [16].
  • Mitochondrial function also requires import of proteins from the cytosol via the translocase of the outer and inner membrane (TOM and TIM complexes) [17].

Associations of ARHGEF5 with chemical compounds

  • In NIH 3T3 cells, TIM induced transforming foci, which was inhibited by the ROCK inhibitor Y-27632 or the dominant negative mutants of Rho proteins [12].
  • Initially, human parotid saliva was fractionated on Bio-Gel P60, and fractions were screened for their ability to promote adhesion of S. gordonii to hydroxyapatite [18].
  • No significant differences were detected in the support provided by P-60, F 2000, Miracle Mix or Fuji IX GP groups [19].
  • Five commercially available composite resins--namely, two conventional hybrid composites (Filtek Z100, Z100; Filtek Z250, Z250), a packable composite (Filtek P60, P60), a flowable composite (Filtek Flow, FL), and a nanofill composite (Filtek Supreme, SU)--were evaluated [20].

Other interactions of ARHGEF5

  • Here, we show that, when expressed in cells, TIM was a potent activator of RhoA [12].
  • Finally, we will discuss the association in humans of TIM-1 and atopy, and the relationship between TIM1, hygiene, and the environment [21].

Analytical, diagnostic and therapeutic context of ARHGEF5

  • The human transforming gene TIM has been mapped to human chromosome 7 region q33-->q35 by fluorescence in situ hybridization with R-banded chromosomes [13].
  • A cell enzyme-linked immunosorbent assay was established allowing quantification of cytoadherent mycoplasmas detected by one of the following MAbs: four MAbs directed against P100 (molecular weight, about 100,000), three MAbs against P80, one MAb against P60, and three MAbs against P50 [22].
  • Finally, vaccination with inactivated influenza virus with TIM-1 antibody results in the significant (P < 0.001) induction of proliferation and IFN-gamma production upon stimulation with one of three serologically distinct strains [23].
  • The analysis established significantly lower thickness values for adult-lesioned as compared to (a) P30, P60 and control groups at AP +14, (b) P30 group at 7 planes along a range of AP +9 to AP +3, and (c) P10 and P60 groups at AP +6 [24].
  • On the whole, the present study reveals that the weak interactions contribute to the global stability of (alpha/beta)(8) TIM-barrel proteins in an environment-specific manner, which can possibly be exploited for protein engineering applications [25].


  1. Expression and molecular characterization of alternative transcripts of the ARHGEF5/TIM oncogene specific for human breast cancer. Debily, M.A., Camarca, A., Ciullo, M., Mayer, C., El Marhomy, S., Ba, I., Jalil, A., Anzisi, A., Guardiola, J., Piatier-Tonneau, D. Hum. Mol. Genet. (2004) [Pubmed]
  2. Response of the methionine synthase system to short-term culture with homocysteine and nitrous oxide and its relation to methionine dependence. Fiskerstrand, T., Ueland, P.M., Refsum, H. Int. J. Cancer (1997) [Pubmed]
  3. Crystal structure of alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase: insight into the active site and catalytic mechanism of a novel decarboxylation reaction. Martynowski, D., Eyobo, Y., Li, T., Yang, K., Liu, A., Zhang, H. Biochemistry (2006) [Pubmed]
  4. P60-c-src suppresses apoptosis through inhibition of caspase 8 activation in hepatoma cells, but not in primary hepatocytes. De Toni, E.N., Kuntzen, C., Gerbes, A.L., Thasler, W.E., Sonuc, N., Mucha, S.R., Camaj, P., Bruns, C., Göke, B., Eichhorst, S.T. J. Hepatol. (2007) [Pubmed]
  5. Neonatal neurosteroid administration results in development-specific alterations in prepulse inhibition and locomotor activity: neurosteroids alter prepulse inhibition and locomotor activity. Gizerian, S.S., Moy, S.S., Lieberman, J.A., Grobin, A.C. Psychopharmacology (Berl.) (2006) [Pubmed]
  6. Interactions between nociceptive and non-nociceptive afferent projections to cerebral cortex in humans. Rossi, A., Decchi, B., Groccia, V., Della Volpe, R., Spidalieri, R. Neurosci. Lett. (1998) [Pubmed]
  7. TIM Family of Genes in Immunity and Tolerance. Kuchroo, V.K., Meyers, J.H., Umetsu, D.T., Dekruyff, R.H. Adv. Immunol. (2006) [Pubmed]
  8. Human TIM-1 Associates with the TCR Complex and Up-Regulates T Cell Activation Signals. Binné, L.L., Scott, M.L., Rennert, P.D. J. Immunol. (2007) [Pubmed]
  9. Age-dependent changes in long-term seizure susceptibility and behavior after hypoxia in rats. Jensen, F.E., Holmes, G.L., Lombroso, C.T., Blume, H.K., Firkusny, I.R. Epilepsia (1992) [Pubmed]
  10. Ontogenesis of morphine-induced behavior in the cat. Burgess, J.W., Villablanca, J.R. Brain Res. (2007) [Pubmed]
  11. Expression cDNA cloning of a novel oncogene with sequence similarity to regulators of small GTP-binding proteins. Chan, A.M., McGovern, E.S., Catalano, G., Fleming, T.P., Miki, T. Oncogene (1994) [Pubmed]
  12. TIM, a Dbl-related protein, regulates cell shape and cytoskeletal organization in a Rho-dependent manner. Xie, X., Chang, S.W., Tatsumoto, T., Chan, A.M., Miki, T. Cell. Signal. (2005) [Pubmed]
  13. Assignment of the human TIM proto-oncogene to 7q33-->q35. Takai, S., Chan, A.M., Yamada, K., Miki, T. Cancer Genet. Cytogenet. (1995) [Pubmed]
  14. Position and time specify the migration of a pioneering population of olfactory bulb interneurons. Tucker, E.S., Polleux, F., Lamantia, A.S. Dev. Biol. (2006) [Pubmed]
  15. Distinct patterns of gene expression in the left and right hippocampal formation of developing rats. Moskal, J.R., Kroes, R.A., Otto, N.J., Rahimi, O., Claiborne, B.J. Hippocampus. (2006) [Pubmed]
  16. Timecourse of development of the wallaby trigeminal pathway: III. Thalamocortical and corticothalamic projections. Marotte, L.R., Leamey, C.A., Waite, P.M. J. Comp. Neurol. (1997) [Pubmed]
  17. Prevention of the ischemia-induced decrease in mitochondrial Tom20 content by ischemic preconditioning. Boengler, K., Gres, P., Cabestrero, A., Ruiz-Meana, M., Garcia-Dorado, D., Heusch, G., Schulz, R. J. Mol. Cell. Cardiol. (2006) [Pubmed]
  18. Salivary amylase promotes adhesion of oral streptococci to hydroxyapatite. Scannapieco, F.A., Torres, G.I., Levine, M.J. J. Dent. Res. (1995) [Pubmed]
  19. A comparative evaluation of four restorative materials to support undermined occlusal enamel of permanent teeth. Prabhakar, A.R., Thejokrishna, P., Kurthukoti, A.J. Journal of the Indian Society of Pedodontics and Preventive Dentistry. (2006) [Pubmed]
  20. Dynamic viscoelastic behavior of dental composites measured by Split Hopkinson pressure bar. Tanimoto, Y., Nishiwaki, T., Nemoto, K. Dental materials journal. (2006) [Pubmed]
  21. Regulation of tolerance in the respiratory tract: TIM-1, hygiene, and the environment. Umetsu, D.T., Dekruyff, R.H. Ann. N. Y. Acad. Sci. (2004) [Pubmed]
  22. Cytoadhesins of Mycoplasma hominis. Henrich, B., Feldmann, R.C., Hadding, U. Infect. Immun. (1993) [Pubmed]
  23. Vaccination with cell immunoglobulin mucin-1 antibodies and inactivated influenza enhances vaccine-specific lymphocyte proliferation, interferon-gamma production and cross-strain reactivity. Soo Hoo, W., Jensen, E.R., Saadat, A., Nieto, D., Moss, R.B., Carlo, D.J., Moll, T. Clin. Exp. Immunol. (2006) [Pubmed]
  24. Regional age-dependent effects of hemineodecortication upon contralateral neocortical thickness: comparison with other measures of cortical size. Schmanke, T.D., Villablanca, J.R. Dev. Neurosci. (1999) [Pubmed]
  25. Exploring the environmental preference of weak interactions in (alpha/beta)8 barrel proteins. Chakkaravarthi, S., Babu, M.M., Gromiha, M.M., Jayaraman, G., Sethumadhavan, R. Proteins (2006) [Pubmed]
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